Guidance on “Risk Analysis”




      Dr. Nishodh Saxena
Introduction
Risk
  “Probable rate of occurrence of a hazard
  causing harm, and the degree of severity of the
  harm”

Ha...
Introduction
ICH Q9 step 4

•   Risk Analysis
    – “Investigation of available information to identify hazards
      and ...
Introduction
Quality Risk management

 “It is a systematic process for the assessment,
 control, communication and review ...
Introduction
Purpose of “Risk Analysis”

– To identifying, documenting and
  quantifying potential risk to product due to
...
Introduction
Benefits through “Risk Analysis”
– Identification of critical parameter
– Improvement in product quality & sa...
Introduction
Scope of “Risk Analysis”

• Risk analysis is conducted for various activity
  related to manufacturing, testi...
Introduction
Principles for “Risk Analysis”
• “The evaluation of the risk to quality should be
  based on scientific knowl...
ICH Q9’s Sample Process for “Risk Analysis”
                                                                              ...
Step – 1 [Risk Assessment]
• Risk assessment consist of;
   – The identification of Hazard
   – Analysis of risk
   – Eval...
Risk Identification
• Risk identification addresses the “what might
  go wrong?” question, including identifying the
  pos...
Risk analysis
• Risk analysis is a systematic use of information to
  identify specific sources of harm (hazards) and to
 ...
Risk evaluation
• Risk evaluation compares the estimated risk
  against given risk criteria using a quantitative
  or qual...
Step-2 [Risk control]
Risk control describes the actions of implementing risk
   management decisions.
   – What can be do...
Step -3 [Risk communication]

– Risk communication is the exchange or sharing of
  information about risk and risk managem...
Step - 4 [Risk monitoring and review]
– All risk management processes are
 dynamic/iterative. Quality risk management when...
Risk management Tools
1. Process mapping
2. Preliminary Hazard Analysis (PHA)
3. Hazard Analysis of Critical Control Point...
Supporting Statistical Tools
• Design of experiments (DOE)
• Process Capability Analysis
• Control charts:
  1. acceptance...
Integration of Quality Risk Management
                          into operations
 1.   Development (e.g. Specification Set...
Integration of Quality Risk Management
                  into operations (Contd..)
6. Production (e.g. PAT, Validation, in...
How to calculate RPN
RPN = Risk Priority Number
    = Severity index X Frequency Index X Detectability Index
•   Estimatin...
How to calculate RPN (Contd..)
• Estimating frequency index          Index   Severity   Interpretation
                   ...
How to calculate RPN (Contd..)
• Estimating detectability             Index
                                       Value
 ...
How to calculate RPN (Contd..)
• Review of Risk value
  – The calculated risk factor shall be analyzed to
    determine th...
How to calculate RPN (Contd..)
Risk Category                     Risk Factor (RPN)   Interpretation

Unacceptable Risk    ...
Thanks

Quality is the responsibility of each and every
  individual employee of the organization.
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Risk Analysis

  1. 1. Guidance on “Risk Analysis” Dr. Nishodh Saxena
  2. 2. Introduction Risk “Probable rate of occurrence of a hazard causing harm, and the degree of severity of the harm” Hazard “A source of potential harm”
  3. 3. Introduction ICH Q9 step 4 • Risk Analysis – “Investigation of available information to identify hazards and estimate risks” – “Risk analysis is the estimation of the risk associated with the identified hazards. It is qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (detectability) also factors in estimation or risk.”
  4. 4. Introduction Quality Risk management “It is a systematic process for the assessment, control, communication and review of risk to the quality of the medicinal product across the product lifecycle”
  5. 5. Introduction Purpose of “Risk Analysis” – To identifying, documenting and quantifying potential risk to product due to any activity, process, testing or change and to determine appropriate measures, with the objective of eliminating or reducing the risk to patient.
  6. 6. Introduction Benefits through “Risk Analysis” – Identification of critical parameter – Improvement in product quality & safety – To find out the risk of any change in activity, process, testing or change. – Reduction in validation cost – Establishes a systematic, well-informed and thorough method of decision making which leads to greater transparency and predictability – Increased knowledge of exposure to risk – Fosters quality by design, continuous improvement and new technology introduction, which generally leads to enhanced product quality
  7. 7. Introduction Scope of “Risk Analysis” • Risk analysis is conducted for various activity related to manufacturing, testing, handling, and distribution of intermediate, drug substance and drug product. • Risk analysis aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug product, biological and biotechnological products.
  8. 8. Introduction Principles for “Risk Analysis” • “The evaluation of the risk to quality should be based on scientific knowledge and ultimately link back to the protection of the patient” • The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk.”
  9. 9. ICH Q9’s Sample Process for “Risk Analysis” Initiate Risk Management Process Risk Assessment Risk Analysis Risk Management tools & statistic toolbar Risk Evaluation (Resources, Interfaces & Line functions) Risk Control Risk Mitigation (incl. elimination and avoidance) [Severity] Risk Reduction [Probability] Risk Acceptance Risk Communication Output / Results of the Review Risk Management Process (e.g. Inspections/Audits, Complaints) No additional risk
  10. 10. Step – 1 [Risk Assessment] • Risk assessment consist of; – The identification of Hazard – Analysis of risk – Evaluation of risk • Quality Risk assessment begin with Risk question – What might go wrong ? (Carry out Risk analysis) – What is the probability it will go wrong? (Determine probability) – What are the consequences (Determine severity)
  11. 11. Risk Identification • Risk identification addresses the “what might go wrong?” question, including identifying the possible consequences.
  12. 12. Risk analysis • Risk analysis is a systematic use of information to identify specific sources of harm (hazards) and to estimate the risk. • 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 harms. In some risk management tools, the ability to detect the harm also factors in the estimation of risk.
  13. 13. Risk evaluation • Risk evaluation compares the estimated risk against given risk criteria using a quantitative or qualitative scale to determine the significance of the risk.
  14. 14. Step-2 [Risk control] Risk control describes the actions of implementing risk management decisions. – What can be done to mitigate and reduce risks? – What options for controlling risks are available? – What are the impacts of current risk management decisions on future options for risk management? • Risk mitigation focuses on a reduction of severity of harm. • Risk reduction focuses on the reduction of probabilities of occurrence of harm and detection of harm. • Risk acceptance is a decision to accept risk, i.e., no additional risk control activities are necessary at that time.
  15. 15. Step -3 [Risk communication] – Risk communication is the exchange or sharing of information about risk and risk management between the decision maker and other stakeholders. The information can relate to the existence, nature, form, probability, severity, acceptability, treatment, detectability or other aspects of risks to quality. – The communication among stakeholders concerning quality risk management decisions can be made through existing channels
  16. 16. Step - 4 [Risk monitoring and review] – All risk management processes are dynamic/iterative. Quality risk management when applied should benefit from new knowledge with each decision cycle and used to enhance future decisions allowing for continuous improvement.
  17. 17. Risk management Tools 1. Process mapping 2. Preliminary Hazard Analysis (PHA) 3. Hazard Analysis of Critical Control Points (HACCP) 4. Hazard Operability Analysis (HAZOP) 5. Fault tree analysis (FTA) 6. Failure Mode Effects Analysis (FMEA) 7. Failure Mode, Effects and Criticality Analysis (FMECA) 8. Risk Ranking and Filtering 9. Informal Risk Management 10. Taguchi, variation risk management method
  18. 18. Supporting Statistical Tools • Design of experiments (DOE) • Process Capability Analysis • Control charts: 1. acceptance control charts. 2. Shewart control charts. 3.Accumulative sum charts
  19. 19. Integration of Quality Risk Management into operations 1. Development (e.g. Specification Setting, Test Method Selection and process development). 2. Regulatory scrutiny during pre and post approval. 3. As a component of Quality systems ( e.g. Auditing, Deviations/Discrepancies, Complaints & Recall Management, Change management) 4. Facility systems management ( e.g. Design, Hygiene, Qualification, environmental control, Preventative maintenance and Computerized systems) 5. Materials Management (e.g. Supply chain, Assessment and evaluation of suppliers and contract manufacturers, procurement and release of material)
  20. 20. Integration of Quality Risk Management into operations (Contd..) 6. Production (e.g. PAT, Validation, in- process sampling, testing, reporting and trending) 7. Laboratory controls (e.g. validation, testing, methods development, stability). 8. Packaging and labeling (e.g. Selection of container closure system and label controls). 9. Regulatory Authority Activities
  21. 21. How to calculate RPN RPN = Risk Priority Number = Severity index X Frequency Index X Detectability Index • Estimating severity index – Severity of the failure shall be estimated based on the effect it may have on the process/product /patient – Assign a quantitative value to the possible effect of each hazard according to the scale show in Table -1 Index Value Severity Interpretation 3 Critical May cause serious/critical effect. High risk to safety and efficacy of the product 2 Major May cause adverse effect directly or indirectly 1 Minor No potential of adverse effect
  22. 22. How to calculate RPN (Contd..) • Estimating frequency index Index Severity Interpretation Value – Estimate frequency index based on the frequency of 3 High Will occur: Expected to occur or has occurred occurrence of each identified frequently (multiple times) cause. in the past with similar product types. – Frequency may be interpreted as probability of occurrence 2 Moderate Likely to occur: Has whose quantitative value shall occurred in past and can be be assigned based on the scale expected to occur if action is not taken to correct or shown in table -2. prevent 1 Low Unlikely to occur: No record of Previous occurrence and it not expected to occur
  23. 23. How to calculate RPN (Contd..) • Estimating detectability Index Value Estimated Detectability Risk Interpretation – Assign detectability 3 Not detectable High There are no controls in place designated to detect index based on ; the defect or failure mode • The ability to detect the 2 Moderately Mode Current method may Detectable rate identify the failure. event prior to or during its Procedures, tests are occurrence and thereby designated to increase the likelihood of detection. preventing the hazard of where the detection method is test, the test is effect. well characterized and • Assign quantitative value validated for detectability based on 1 Readily or Low Failure are detected with highly high degree of probability the scale shown in Table-3 detectable before the product is a test, the test is well characterized and validated
  24. 24. How to calculate RPN (Contd..) • Review of Risk value – The calculated risk factor shall be analyzed to determine the need for mitigation, CA/PA, etc. – Table-4 describes recommended action based on a calculated risk factor. – After mitigation/taking appropriate action to reduce the risk for a given operation/activity, the FMEA may be carried out again to calculate the RPN.
  25. 25. How to calculate RPN (Contd..) Risk Category Risk Factor (RPN) Interpretation Unacceptable Risk > 21 Risk too sever to be tolerated. A risk in this region must be reduced to ALARP region to implementation of the activity/product etc. ALARP region of acceptable risk > 6 -21 Tolerable risk, only if the reduction is impractical or cost of reduction grossly disproportionate to improvement. Acceptable risk Negligible Risk 1–6 Risk is Negligible. Mitigation not necessary
  26. 26. Thanks Quality is the responsibility of each and every individual employee of the organization.
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