1. Quality Risk Management
Tony Gould

2. Introduction
Risk management is not new – we do it informally all the time
Military Standard 1629 dated 1974 regarding formal risk management
Risk management has been used in the medical device, telecommunications, aerospace and car industries for many years

3. Introduction
Risk management has also been part of the pharma industry for many years:
GMP requirements are designed to address risk. For example, the specific GMP requirements for sterile products are designed to mitigate the risk of sterility failure
In some cases, GMP specifies a risk based approach. For example, "a risk assessment approach should be used to determine the scope and extent of validation required" (WHO Annex 4, )
Specifications in pharmacopoeial monographs include tests for known potential contaminants

4. Introduction Greater use of risk management tools in the future
We must accept this and prepare
From a GMP point of view, we are only concerned with risks associated with quality, safety and efficacy – quality risk management
Organisations use risk approaches in other areas, e.g. to ensure resources are utilised in the most effective way. Also applicable to inspectorates

5. GMP requirement
A system for quality risk management should be included in the quality assurance system
Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.
The quality risk management system should ensure that:
the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; and
the level of effort, formality and documentation of the quality isk management process is commensurate with the level of risk.
1.2 – 1.5

6. QRM - the dangers
There is a desired outcome and risk management is used to justify it
Invalid assumptions – suit the desired outcome
Cost reduction (increased profits) is often the real reason that many risk assessments are done
Cost reduction may be a secondary outcome
Variable tolerance of risk

7. QRM – from an inspectors point of view
Be prepared so that the process is understood
Have sufficient knowledge to understand what has been done and challenge assumptions, omissions etc
Be clear about when QRM is not appropriate
Be flexible and accept the outcome of a scientifically sound QRM exercise
If done properly there should be increased assurance of quality (and possibly cost savings)

8. What is QRM
"Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product across the product lifecycle." (ICH Q9)

9. Typical QRM process What might go wrong or has gone wrong?
What is likelihood or probability?
What are the consequences (severity)?
What is the level of risk? Any mitigating factors?
Risk Review R i s k C o m u n c a t
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 M g e l

10. Risk assessment
"A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards." (ICH Q9)

11. Risk assessment terms Risk identification Risk analysis
Use of information to identify hazards or potential risks
Historical data, theoretical analysis, informed opinions
Risk analysis
Estimation of risk associated with identified hazards
Qualitative or quantitative
Links probability and severity
In some tools, includes detectability

12. Risk analysis - probability
A simple qualitative tool:
P – Probability of Occurrence
Likely to occur
High
May occur
Medium
Unlikely to occur
Low
Very unlikely to occur
Remote

13. Risk analysis - severity
A simple qualitative tool:
S – severity level if event occurs
Serious GMP non-compliance Patient injury possible
Critical
Significant GMP non-compliance Impact on patient possible
Moderate
Minor GMP non-compliance No patient impact
Minor

14. Risk assessment terms Risk evaluation
Compares identified and analysed risk against criteria
Considers probability, severity and detectability
Output can be qualitative (high, medium or low)
Output can be quantitative (probability x severity x detectability)
Quantitative provides a relative ranking – prioritises risk

15. Risk evaluation Risk = P x S
A simple risk table with risk acceptability criteria:
Risk = P x S
Critical
Moderate
Minor
Severity
Probability
Intolerable risk
Unacceptable risk
High
Acceptable risk
Medium
Low
Remote

16. Risk evaluation
Modify evaluated risk according to existing detection controls
Detectability:
High – the control is likely to detect the negative event or its effects
Medium – the control may detect the negative event or its effects
Low – the control is not likely to detect the negative event or its effects
Zero – no detection control in place

17. Risk evaluation Risk definitions:
 Intolerable – work to eliminate the negative event or introduce detection controls is required as a priority
 Unacceptable – work to reduce the risk or control the risk to an acceptable level is required
 Acceptable – the risk is acceptable and no risk reduction or detection controls are required

18. Risk control "Actions implementing risk management decisions" (ICH Q9)
Includes risk reduction (if applicable) and risk acceptance

19. Risk control terms Risk reduction Risk acceptance
Actions taken to lessen the probability of occurrence of harm and the severity of that harm
Typically CAPA and change control
Risk acceptance
The decision to accept risk
If risk reduction action taken, follows re-analysis and evaluation

20. Risk Review
"Review or monitoring of output/results of the risk management process considering (if appropriate) new knowledge and experience about the risk." (ICH Q9)
Ensures nothing has changed to affect the QRM assumptions, output and conclusions
Consider during product review

21. QRM tools – some of them!
Basic risk management facilitation methods (flowcharts, check sheets etc.);
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.

22. Potential applications
Quality Management (e.g. self-inspection, training, complaints, deviations, change control)
Development (ICH Q8)
Facilities, Equipment and Utilities (e.g. design, qualification, hygiene, calibration, computers)
Materials Management (e.g. supplier assessment, storage)
Production (e.g. validation, in-process sampling and testing)
Laboratory Control and Stability Studies (e.g. OOS, retest periods, validation)
Packaging and Labelling (e.g. package design, label control)