Risk Assessment tools used by Pharmaceutical Industry
Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Quality risk assessments begin with a well-defined problem description or risk question. When the risk in question is well defined, an appropriate risk management tool and the types of information that will address the risk question will be more readily identifiable.
Risk identification is a systematic use of information to identify hazards referring to the risk question or problem description.
Information can include
- Historical data,
- Theoretical analysis,
- Informed opinions, and
- The concerns of stakeholders.
- Risk identification addresses the “What might go wrong?” question, including identifying the possible consequences.
This provides the basis for further steps in the quality risk management process.
Risk analysis is the estimation of the risk associated with the identified hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harm. The ability to detect harm (detectability) also factors in the estimation of risk.
Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk evaluations consider the strength of evidence for all three of the fundamental questions.
Three fundamental questions are often helpful:
- What might go wrong?
- What is the likelihood (probability) it will go wrong?
- What are the consequences (severity)?
Risk control includes decision-making to reduce and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level. Risk control might focus on the following questions:
- Is the risk above an acceptable level?
- What can be done to reduce or eliminate risks?
- What is the appropriate balance among benefits, risks, and resources?
- Are new risks introduced as a result of the identified risks being controlled?
The most common risk assessment Tools used by Pharmaceutical Industry for their quality issues include –
- Basic Risk Management Facilitation Methods
- Failure Mode Effects Analysis (FMEA)
- Failure Mode, Effects and Criticality Analysis (FMECA)
- Fault Tree Analysis (FTA)
- Hazard Analysis and Critical Control Points (HACCP)
- Hazard Operability Analysis (HAZOP)
- Preliminary Hazard Analysis (PHA)
- Risk Ranking and Filtering
- Supporting Statistical Tools
Below is a brief summary of each of these five risk assessment tools.
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:
- Check Sheets
- Process Mapping
- Cause and Effect Diagrams (also called an Ishikawa diagram or fishbone diagram)
- The Five Whys
Cause and Effect Analysis
A visual diagram that displays the causes of an event. It’s often used in manufacturing and product development to lay out the different steps in a process, demonstrate where quality control issues might arise, and determine which resources are needed at certain times.
The causal factors (fish bones) attribute to a final outcome (fish head).
Causes are grouped into broad categories such as Man, Materials, Machinery, Methods, and Miscellaneous so as to cover all possible origins of the issue.
The Five Whys
The Five Whys technique is a simple, iterative, and team-driven process that aims to uncover the root cause of a problem or defect by interrogating the issue by asking ‘Why?’ five times.
Each answer forms the basis of the next question, and the final ‘why?’ should lead to corrective action.
Asking the ‘5 Whys’ is useful in determining the root cause of an issue during Risk Assessment.
Failure Mode Effect Analysis (FMEA)
Failures are prioritized according to how serious their consequences are, how frequently they occur, and how easily they can be detected.
It also documents current knowledge and actions about the risks of failures, for use in continuous improvement.
It uses clear assignments of responsibilities and a timeline for each action.
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). 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 Uses:- 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.
Failure Mode Effects Analysis (FMEA)
FMEA 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 Uses: – 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.
Fault Tree Analysis (FTA)
A graphical tool to explore the causes of system-level failures.
A top-down, deductive failure analysis.
It uses Boolean Logic to combine a series of lower (component) level events to find out the cause of a top-level event (such as system-level failure.)
Consists of two elements “events” and “logic gates” which connect the events to identify the cause of the top undesired event.
Easier method than FMEA since it incorporates all possible system failures of an undesired top event. FMEA, in contrast, conducts analysis to find all possible system failure modes irrespective of their severity.
The FTA tool is an approach that assumes failure of the functionality of a product or process. This tool evaluates system (or subsystem) 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 Uses: – 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.
Hazard Analysis and Critical Control Points (HACCP)
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and safety. It is a structured approach that applies technical and scientific principles to analyze, evaluate, prevent, and control the risk or adverse consequences of hazards 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 Uses: – 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 the 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 (HAZOP)
HAZOP 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 Uses: – 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.
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 possibility that the risk event happens,
2) the qualitative evaluation of the extent of possible injury or damage to health that could result
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 Uses: – 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.
Risk Ranking AND Filtering
Identified risks are assessed either quantitatively or qualitatively, to ascertain which ones have the highest likelihood of occurrence and which ones have the greatest consequence of occurrence, this ranks the risks in overall order of importance.
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 Uses: – 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.
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:
(i) 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
(ii) Design of Experiments (DOE)
(v) Process Capability Analysis
ICH guideline Q9 on quality risk management
Q9 Quality Risk Management