Integration into Industry and Regulatory Operations

Quality risk management is the foundation for science-based decisions when integrated into a quality management system (QMS). It does not obviate industry’s obligations to comply with regulatory requirements. It can facilitate better and more-informed decisions and may provide regulators with greater assurance of a company’s ability to address potential risks. It may affect the extent and level of direct regulatory oversight.

The degree of rigor and formality used in quality risk management should be commensurate with the complexity and/or criticality of the issue. Quality risk management should be integrated into existing operations and documented appropriately. Finally, training of personnel provides for greater understanding of decision-making processes and builds confidence in quality risk management outcomes.

Methods and Tools

Basic Risk Management Facilitation Methods

Basic risk management facilitation methods include flowcharts, check sheets, process maps, and cause-and-effect diagrams (that is, the Ishikawa diagram, or fishbone diagram).

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) includes the evaluation of potential failure modes and their effect on outcomes. It methodically breaks down the analysis of complex processes into manageable steps; risk reduction can then be used to eliminate, contain, reduce, or control failures.

The potential areas of use for FMEA are to prioritize risks and monitor the effectiveness of risk control activities. It can be applied to equipment and facilities, and might be used to analyze a manufacturing operation and its effect on product or process. It identifies elements/operations within the system that render it vulnerable. The output or results of FMEA can be used as a basis for design or further analysis, or to guide resource deployment.

Failure Mode, Effects and Criticality Analysis

Failure mode, effects and criticality analysis (FMECA) is extended to investigate the degree of severity of the consequences, probabilities of occurrence, and detectability. It can identify places for additional preventive actions.

Potential areas of use for FMECA application in the pharmaceutical industry should be primarily for failures and risks associated with manufacturing processes; however, it is not limited to this application. The output of an FMECA is a relative risk score for each failure mode, which is used to rank the modes on a relative risk basis.

Fault Tree Analysis

Fault tree analysis (FTA) evaluates system (or subsystem) failures one at a time, represented pictorially in the form of a branching tree of fault modes. At each level in the tree, combinations of fault modes are described with logical operators (for example, AND, OR). FTA relies on experts’ process understanding to find causes. A potential area of use for FTA can be to establish the pathway to the root cause of the failure. FTA can be used to investigate complaints or deviations to fully understand their root cause and to ensure that intended improvements will resolve the issue and not lead to other issues. FTA is an effective tool for evaluating how multiple factors affect a given issue. The output of an FTA includes a visual representation of failure modes. It is useful both for risk assessment and in developing monitoring programs

Hazard Analysis and Critical Control Points

Hazard analysis and critical control points (HACCP) is used to manage risks with physical, chemical, and biological hazards. HACCP has seven steps:

1. Conduct a hazard analysis and identify preventive measures for each step of the process.

2. Determine the critical control points.

3. Establish critical limits.

4. Establish a system to monitor the critical control points.

5. Establish the corrective actions to be taken when monitoring indicates that the critical control points are not in a state of control.

6. Establish a system to verify that the HACCP system is working effectively.

7. Establish a record-keeping system.

Potential areas of use for HACCP might be to identify and manage risks associated with physical, chemical, and biologic hazards (including microbiological contamination). HACCP is useful when product and process understanding is sufficiently comprehensive to support identification of critical control points. The output of a HACCP analysis is risk management information that facilitates monitoring of critical points not only in the manufacturing process but also in other life cycle phases.

Hazard Operability Analysis

Hazard operability analysis (HAZOP) is used primarily to evaluate process safety hazards. It is a systematic brainstorming technique for identifying hazards using guide words (for example, no, more, other than, part of). HAZOP is for risk events caused by design or operating deviations. Potential areas of use for HAZOP are manufacturing processes, including outsourced production and formulation, and the upstream suppliers, equipment, and facilities for drug substances and drug products. It has been used primarily in the pharmaceutical industry for evaluating process safety hazards. As is the case with HACCP, the output of a HAZOP analysis is a list of critical operations for risk management. This facilitates regular monitoring of critical points in the manufacturing process.

Preliminary Hazard Analysis

Preliminary hazard analysis (PHA) is the application of experience or knowledge of a hazard to identify future hazards. This tool consists of identification of the possibility that the risk event happens, qualitative evaluation of the extent of possible injury or damage to health that could result, relative ranking of the hazard using a combination of severity and likelihood of occurrence, and identification of possible remedial measures.

Potential areas of use for PHA might be analysis of existing systems or prioritizing hazards where circumstances prevent a more extensive technique from being used. It can be used for product, process, and facility design, as well as to evaluate the types of hazards for the general product type, then the product class, and finally the specific product. PHA is most commonly used early in the development of a project when little information on design details or operating procedures is available; thus, it will often be a precursor to further studies. Typically, hazards identified in the PHA are further assessed with other risk management tools.

Risk Ranking and Filtering

Risk ranking and filtering is a tool for comparing and ranking risks including filters (for example, cutoff scores). Potential areas of use include prioritizing manufacturing sites for inspection/audit by regulators or industry. Risk ranking methods are particularly helpful in situations in which the portfolio of risks and the underlying consequences to be managed are diverse and difficult to compare using a single tool. Risk ranking is useful to management in evaluating both quantitatively assessed and qualitatively assessed risks within the same organizational framework.

Supporting Statistical Tools

These tools support data assessment and facilitate decision making. The most common statistical tools are control charts, design of experiments (DOE), histograms, Pareto charts, process capability analysis, FTA, FMEA, and HACCP.

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