Use of QRM to Quantify Particulate Contamination Risks

Transcription

1 Use of QRM to Quantify Particulate Contamination Risks PDA Ireland Chapter Quality Risk Management Seminar NIBRT Mount Merrion, Blackrock, Co. Dublin Chris Roberts

2 Agenda Background Objective / Scope Execution Methodology Risk Identification Severity Probability of Occurrence Summary Risk Control Risk Reduction Risk Acceptance QRM Conclusion Questions? 2

3 Background State of the Art Vaccines and Biologics Facility Sterile (Aseptic) filling of vials and syringes Single Use Technology (tubing, manifolds) and Ready to Use Components QRM Team Cross-functional team - Facilitators, QRM Lead, Technical Engineering, Operations, Quality Assurance, Quality Control, Supply Chain and Facilities 3

4 Objective / Scope Objective The goal of the risk assessment was to identify potential sources and entry points of visible particulate. Inherent to the process and equipment used for the pooling and filling process. In order to quantify the risk in terms of potential impact to product quality and identify opportunities to further reduce these risks. Scope Review of risks and effectiveness of controls associated with the routine mfg. operations including: DS receipt, Product contact materials (SU tubing, stoppers, vials etc) Equipment cleaning and sterilisation Material transfers, filtration, pooling, filling Maintenance, Cumulative process and equipment changes OutofScope Glass breakage, stopper coring, sub-visible particulate and DS supply 4

5 Risk Assessment Process Methodology The PHA (Process/Preliminary Hazard Analysis) tool was used to assess potential risks associated with visible particulates in the final filled container. Semi-quantitative tool of analysis that is based on applying prior experience or knowledge of a hazard in order to: Identify all potential hazards, situations and events that may cause potential harm to product quality and/or patient safety Rank the potential risk according to its severity of harm, probability of occurrence, and (as applicable) the ability to detect the hazard. Document controls for preventing the failure mode and/or its causes Identify required hazard controls and follow-up actions. PHA considers Severity; Occurrence; Detection 5

6 PHA: Key Definitions Hazard Harm Hazardous Situation or Event Severity Probability Risk Potential source of harm (ICH Q9, ISO/IEC Guide 51) Damage to health, including the damage that can occur from loss of product quality or availability (ICH Q9) Circumstances in which people, property or the environment are exposed to a hazard Measure of the possible consequences of a Hazard (ICH Q9) Extent to which an event is likely to occur (ISO/IEC Guide 73) Combination of the probability of occurrence of harm and the severity of that harm 6

7 Execution Phase Risk Identification: Risk identification answers the question of What might go wrong? and includes identification of the possible consequences of the hazard. Subject Matter Experts (SMEs) developed a library of common hazards / harms, and assessed their severity for potential product quality impact The potential hazards and hazardous causes were identified based on SME s experience with the processes. Risk identification performed as several steps to ensure a comprehensive identification of risks. Intent - To develop a library of common hazards, harms, and assessment of their severity for potential product quality impact. Included observation and evaluation of activities in the field. Developed a process map to identify all steps in the manufacturing process. For each step of the process, identify relevant risk categories. Identify potential hazards for the process step and risk category (as applicable). Classify harm to product quality as potential of the presence of particulates 7

8 Execution Phase Risk Identification: Hazard is an immediate output from the Process/System that directly causes harm Hazard could be energy, material or piece of information (data) Harm is described in terms of impact to product quality Identify the item/process step within the Process/System Identify hazards associated with a component of the Process/System Identify known hazards (based on experience, reported events, complaints, accidents, literature etc.) Identify harm caused by the hazard to product quality and/or patient safety Identify hazardous situations that would cause the hazard to result in harm Identify current controls in place to prevent the hazard Identify current controls in place to detect the hazard 8

9 Execution Phase Severity (S): The severity (S) of each hazard was evaluated based on the harm, or effect of hazard, on product quality. Team assessed the consequences of the identified hazards should they result in visible particulates in the final product. The severity was analyzed separately from the probability of occurrence (O). The severity of harm was scored assuming no controls in place. Severity of the harm was predetermined to be an eight (8), with a critical impact that may lead to serious/critical regulatory observations and/or lead to a product recall if any of the harms were realized. 9

10 Execution Phase Probability of Occurrence (O): The probability of occurrence (O) was evaluated based on technical input from the SMEs and process data. Based on a predefined scoring criteria. Scoring considered prevention controls Design, elements and aspects of the physical equipment that control risk Quality system controls, Specifications, SOP s, training. Qualification / Validation controls. Downstream visual inspection detection methods were not factored for scoring evaluation of probability of occurrence. Developed a customized scoring definition that was relevant for the process being assessed. SCORE CATEGORY CRITERIA CUSTOMISED CRITERIA 10 VERY HIGH CERTAIN TO OCCUR ROUTINELY 50% OF THE VIAL IN 1 BATCH CONTAIN A PARTICLE 8 HIGH OCCURS FREQUENTLY 1 VIAL IN 1000 CONATINS A PARTICLE 6 MODERATE OCCURS OCCASIONALLY 1 VIAL IN 1 BATCH CONTAINS A PARTICLE 4 LOW HAS NOT OCURRED OFTEN 1 VIAL IN 2 BATCHES CONTAINS A PARTICLE 2 REMOTE EXTREMELY UNLIKELY TO OCCUR 1 VIAL IN 3 BATCHES CONTAINS A PARTICLE Calculate Risk Priority Number 1 (RPN1) : Severity x Probability of Occurrence = Risk Priority Number 1 (RPN1) 10

11 Risk Evaluation (RPN1) Risk Matrix (RPN1) Occurrence Very High High Severity 6 Moderate Low Remote High: Require Risk Control Action(s) Medium: Reduce Risk to As Low as Reasonably Practicable (ALARP) Low: Acceptable If either Severity or Probability of Occurrence cannot be reduced further, then detection mechanisms must be assessed (to determine the ability to detect the risk), using RPN 2 11

12 Execution Phase Detection (D): Design and non-design related controls that serve to detect hazards, hazardous situations and harm were considered in assigning detection scores. Controls that serve to improve detectability as well as reduce the probability of occurrence were considered in both the detection and occurrence ratings. Both direct and indirect detection controls were considered for each process step. Vial washing through filling and stoppering was considered to be one integrated step. Automated vial inspection was considered a separate step The detection score for filling activities that solely relied on automated visual inspection was scored as a six (6). SCORE CATEGORY CRITERIA 10 REMOTE THERE IS NO ESTABLISHED INSPECTION, TESTING OR MONITORING IN PLACE TO DETECT THE FAILURE 8 LOW THERE IS LIMITED INSPECTION, TESTING OR MONITORING IN PLACE. DETECTION AND MULTIPLE FAILURE MAY GO UNDETECTED BETWEEN CONSECUTOVE STEPS 6 MODERATE SOME INSPECTION, TESTING OR MONITORING IS IN PLACE. DETECTION IS DELAYED AND SINGLE FAILURE COULD GO UNDETECTED BETWEEN CONSECUTIVE STEPS 4 HIGH INSPECTION, TESTING OR MONITORING IS IN PLACE. THERE IS A HIGH PROBABILITY THAT THE FAILURE WILL BE DETECTED WITHIN THE STEP Calculate Risk Priority Number 2 (RPN2) : Severity x Probability of Occurrence x Likelihood of Detection = Risk Priority Number 2 12

13 Risk Evaluation (RPN 2) Risk Category (RPN1) Detection Risk (D) High Risk Risk Score Medium Risk Low Risk Risk reduction actions are required. If a high risk cannot be further reduced, formal acceptability of risk by appropriate decision makers (including Quality) is required and documented. Further risk reduction must be investigated to determine if risk can be reduced. If risk cannot be reduced, the risk may be accepted and the acceptance decision must be properly documented. Risk is acceptable. No further action is required. 13

14 Risk Assessment Summary 115 potential hazards that may impact product quality were identified. For twelve (12) of the risks identified, risk analysis was not performed as the current controls ensure that there can be no impact to product quality as the hazardous situation either cannot occur or product would be discarded upon detection. Majority of the risks identified were related to potential for particulate to enter the process via materials / components (wipes / Tyvek etc). The results of the 103 risks are summarized as follows: RISK CATEGORY (Based on RPN 2) NUMBER OF RISKS HIGH 34 MEDIUM 35 LOW 34 14

15 Risk Control The process by which decisions are reached and measures are implemented to reduce or maintain risk within specified levels. Risk Reduction Reduce occurrence by implementing controls to the process/system. Make design changes to eliminate the harm (preferred). Risk Acceptance Decision to accept risk. Formal acceptance of the risk(s) by appropriate decision makers. Prevention Proactive Engineer-out Defects Eliminate Root Causes Prevent Defects Detection Retroactive Inspection Mitigate after Event Sort Defect from Accept Output 15

16 Risk Control Precedence of Risk Control Response Remove Risk Reduce Severity Reduce Occurrence Increase Detection Communicate Risk Accept Risk Questions Questions to Consider Guidance Is the risk above an acceptable level? What can be done to reduce or eliminate the risk? What is the appropriate balance between benefits/risks/resources? Are new risks introduced as a result of risk reduction measures? Refer to local QRM procedures to determine acceptability criteria. Follow the Precedence of Risk Control Response. Put multiple controls in combination. Focus resources on high risks that can be reduced. Weigh efforts / benefits of controls. Consider RPN values. Include appropriate risk monitoring and review criteria. 16

17 Risk Acceptance Decisions Biggest challenge is overcoming the tendency to accept risks passively or informally. Risk acceptance decisions must be made by appropriate decision makers and associated justification must be documented. Describe acceptable levels State who sets them Rationale for the decisions Process of Risk Control must be iterative to make sure that risks are reduced as much as possible. Residual Risk Risks that remain after all control measures have been implemented or which may result from the implementation of a reduction strategy. 17

18 Particulate QRM Conclusion 115 potential hazards that may impact product quality were identified. For twelve (12) of the risks identified, risk analysis was not performed. Risk Category (based on RPN2) Number of Risks Mitigation Required Risk Accepted High Medium Low Primary Risks Identified: Unflushed fluid contact surfaces Use of Wipes and Tyvek Line Set-up Visual Inspection (increase AQLs) Recommended mitigations prioritized on the site risk register with appropriate actions 18

19 19 Questions?