The purpose of this Annex is to provide a general overview of and references for some of the primary tools that might be used in quality risk management by industry and regulators. The references are included as an aid to gain more knowledge and detail about the particular tool. This is not an exhaustive list. It is important to note that no one tool or set of tools is applicable to every situation in which a quality risk management procedure is used.

I.1 Basic risk management facilitation methods:

Some of the simple techniques that are commonly used to structure risk management by organizing
data and facilitating decision-making are:
 Flowcharts;
 Check Sheets;
 Process Mapping;
 Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram).

I.2 Failure Mode Effects Analysis (FMEA)

FMEA (see IEC 60812) provides for an evaluation of potential failure modes for processes and their likely effect on outcomes and/or product performance. Once failure modes are established, risk
reduction can be used to eliminate, contain, reduce or control the potential failures. FMEA relies on product and process understanding. FMEA methodically breaks down the analysis of complex processes into manageable steps. It is a powerful tool for summarizing the important modes of failure, factors causing these failures and the likely effects of these failures.

Potential Areas of Use(s)

FMEA can be used to prioritize risks and monitor the effectiveness of risk control activities. FMEA 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/ results of FMEA can be used as a basis for design or further analysis or to guide resource deployment.

I.3 Failure Mode, Effects and Criticality Analysis (FMECA)

FMEA might be extended to incorporate an investigation of the degree of severity of the consequences, their respective probabilities of occurrence, and their detectability, thereby becoming a Failure Mode Effect and Criticality Analysis (FMECA; see IEC 60812). In order for such an analysis to be performed, the product or process specifications should be established. FMECA can identify places where additional preventive actions might be appropriate to minimize risks.

Potential Areas of Use(s)

FMECA application in the pharmaceutical industry should mostly be utilized 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.

I.4 Fault Tree Analysis (FTA)

The FTA tool (see IEC 61025) is an approach that assumes failure of the functionality of a product or process. This tool evaluates system (or sub-system) failures one at a time but can combine multiple causes of failure by identifying causal chains. The results are represented pictorially in the form of a tree of fault modes. At each level in the tree, combinations of fault modes are described with logical operators (AND, OR, etc.). FTA relies on the experts’ process understanding to identify causal factors.

Potential Areas of Use(s)

FTA can be used to establish the pathway to the root cause of the failure. FTA can be used to investigate complaints or deviations in order to fully understand their root cause and to ensure that
intended improvements will fully resolve the issue and not lead to other issues (i.e. solve one problem yet cause a different problem). Fault Tree Analysis 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.

I.5 Hazard Analysis and Critical Control Points (HACCP)

HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and safety (see WHO Technical Report Series No 908, 2003 Annex 7). It is a structured approach that applies technical and scientific principles to analyze, evaluate, prevent, and control the risk or adverse consequence(s) of hazard(s) due to the design, development, production, and use of products.

HACCP consists of the following 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 action to be taken when monitoring indicates that the critical control points
are not in a state of control;
6. establish system to verify that the HACCP system is working effectively;
7. establish a record-keeping system.

Potential Areas of Use(s)

HACCP might be used to identify and manage risks associated with physical, chemical and biological hazards (including microbiological contamination). HACCP is most 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.

I.6 Hazard Operability Analysis (HAZOP)

HAZOP (see IEC 61882) is based on a theory that assumes that risk events are caused by deviations from the design or operating intentions. It is a systematic brainstorming technique for identifying hazards using so-called “guide-words”. “Guide-words” (e.g., No, More, Other Than, Part of, etc.) are applied to relevant parameters (e.g., contamination, temperature) to help identify potential deviations from normal use or design intentions. It often uses a team of people with expertise covering the design of the process or product and its application.

Potential Areas of Use(s)

HAZOP can be applied to manufacturing processes, including outsourced production and formulation as well as the upstream suppliers, equipment and facilities for drug substances and drug (medicinal) products. It has also 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.

I.7 Preliminary Hazard Analysis (PHA)

PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure to identify future hazards, hazardous situations and events that might cause harm, as well as to estimate their probability of occurrence for a given activity, facility, product or system.

The tool consists of:

  1. the identification of the possibilities that the risk event happens,
  2. the qualitative evaluation of the extent of possible injury or damage to health that could result and
  3. a relative ranking of the hazard using a combination of severity and likelihood of occurrence, and
  4. the identification of possible remedial measures.

Potential Areas of Use(s)

PHA might be useful when analyzing 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 there is little information on design details or operating procedures; thus, it will often be a precursor to further studies. Typically, hazards identified in the PHA are further assessed with other risk management tools such as those in this section.

I.8 Risk ranking and filtering

Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex systems typically requires evaluation of multiple diverse quantitative and qualitative factors for each risk. The tool involves breaking down a basic risk question into as many components as needed to capture factors involved in the risk. These factors are combined into a single relative risk score that can then be used for ranking risks. “Filters,” in the form of weighting factors or cut-offs for risk scores, can be used to scale or fit the risk ranking to management or policy objectives.

Potential Areas of Use(s)

Risk ranking and filtering can be used to prioritize 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 when management needs to evaluate both quantitatively-assessed and qualitatively-assessed risks within the same organizational framework.

I.9 Supporting statistical tools

Statistical tools can support and facilitate quality risk management. They can enable effective data
assessment, aid in determining the significance of the data set(s), and facilitate more reliable decision
making. A listing of some of the principal statistical tools commonly used in the pharmaceutical
industry is provided:
 Control Charts, for example:
 Acceptance Control Charts (see ISO 7966);
 Control Charts with Arithmetic Average and Warning Limits (see ISO 7873);
 Cumulative Sum Charts (see ISO 7871);
 Shewhart Control Charts (see ISO 8258);
 Weighted Moving Average.
 Design of Experiments (DOE);
 Histograms;
 Pareto Charts;
 Process Capability Analysis