2014_NVF_III_Session_3_Risk_Assessment.pdf

2014_NVF_III_Session_3_Risk_Assessment.pdf
Session 3 Validation, Risk and Criticality Presented by Trevor Schoerie 14 May, 2014
Slide 2 © PharmOut 2014 Validation, Risk and Criticality • In process validation we want to understand and control the variation not the risk. • The “drug” benefit vs risk should have already been determined, (hopefully). “GAMP 5 – Risk Based ……” “We talk about QRM every time we meet!”
Slide 3 © PharmOut 2014 “Process Variation” 1. Sample Variation 2. Analytical Variation? 3. Process Variation – normally associate Is the sample representation of the batch? Blinded samples in lab = STD DEV Real process variation
Slide 4 © PharmOut 2014 This session Using Risk to determine no of batches Risk vs criticality
Slide 5 © PharmOut 2014 How we get to validation….. • New Chemical Entity *Stage 1 data • Generic manufacturer • Contract manufacturer • New manufacturing site – Tech. Transfer • Country where validation is a new requirement • Expansion of regulations, i.e. export to Australia No concurrent release of validation batches No retrospective validation
Slide 6 © PharmOut 2014 Typical validation NCE – Stage 2a/b? Real life Start Registration / QbD
Slide 7 © PharmOut 2014 How many PPQ batches? QTPP CQAs/ CPPs Process Description Analytical Methods SOPs & Batch Records Design Reports FSE Qualified PVMP Training Completed Approved PV Protocols
Slide 8 © PharmOut 2014 Knowledge vs # of PV batches Prior Knowledge Process Design Prior Knowledge PV Process Design PV Comprehensive Prior Knowledge may support fewer PV batches Limited Prior Knowledge may require more PV batches
Slide 9 © PharmOut 2014 How many PPQ batches? This depends on the risk and the following elements: Based on science, experience and justified (documented). Based on statistics.
Slide 10 © PharmOut 2014
Slide 11 © PharmOut 2014 How many PPQ batches? Step 2: Risk Assessment of Control Strategy Step 3: Determine Overall Residual Risk Step 4: Translate Overall Residual Risk into # of PPQ Batches Stage 1 Assessment Stage 2 Activities Prepare PPQ Batches Compare results to Acceptance Criteria Risk Level Acceptable Step 1: Risk Assessment of Product Knowledge & Process Understanding Reference ISPE
Slide 12 © PharmOut 2014 Risk Assessment of Stage 1 Product Knowledge • Analytical understanding of product structure • Mechanistic understanding of product profile • Contextual understanding of CQA’s Process Understanding • Depth of understanding unit operations • Level of knowledge of process response to input variability • Process predictability • Understanding of scale Control Strategy • Application of process/product understanding to production controls • Control of raw material inputs • Equipment capability vs process requirements Assess each CQA Can use: • Risk Charts • Relative level of risk based on RPN • Other QRM tools
Slide 13 © PharmOut 2014 Step 1: Risk Assessment of Product Knowledge Identification of CQA and impact of CQA variation on patient: • Level of understanding of product attributes (i.e. how a particular attribute affects patient safety & efficacy) Product Characterisation: • The strength of the link between the CQA and clinical performance
Slide 14 © PharmOut 2014 Product Knowledge Risk Ranking Product Knowledge Factor Relative Risk Ranking Characteristics of ranking assignments Low Risk Medium Risk High Risk Identification of CQA and impact of CQA variation on patient • Physiochemical/ biological, pharmacokinetic knowledge, and QbD approach used to design the formulation of drug product • Impact of variation on bioavailability explored & understood • CQAs identified and justified • Physiochemical/ biological, pharmacokinetic properties identified • Some exploration of impact of variation • Product specifications established from development trial and error • Impact of variation known only from evaluation of incidents Product Characterisation • Analytical method has direct measurable linkage to clinical performance • Complete product • Analytical method development based on mechanism of action for the therapeutic agent but linkage to clinical performance • Product characterisation measures quality against established empirical limits
Slide 15 © PharmOut 2014 Process Understanding Risk Ranking Process Understanding Factor Relative Risk Ranking Characteristics of ranking assignments Low Risk Medium Risk High Risk Degree of process understanding/ unit operation -First principles understanding: based on an understanding of prevailing mechanisms and rationale -Casual knowledge: that based on what causes interrelationships between variables -Descriptive knowledge: derived only from observation, reflecting basic facts Process predictably and modelling -Models based on first principles -Extension of empirical and mechanistic models -Highly predictable process and scale-up -Use of models derived from basic physical, chemical, biological or microbial mechanisms of observed phenomena -Sufficient knowledge to employ PAT methods, if applicable and desired -Primitive models reflecting only basic understanding of process and scale effects -Process predictability is questionable Table continued on the next slide
Slide 16 © PharmOut 2014 Process Understanding Risk Ranking Process Understanding Factor Relative Risk Ranking Characteristics of ranking assignments Low Risk Medium Risk High Risk Process Response to input variability -Design space identified using multivariate data and statistical methods -Impact of material attributes on product quality explored extensively in development -Material specific CQAs identified and well understood or no material specific CQAs -Well-defined criticality for process based on multivariative experiments -Impact of material attributes on product quality explored to some degree -Material specific CQAs identified-full range of variability not explored in development -Partially defined, primarily through univariate experimentation -Impact of materials attributes to product quality are minimally explored -Materials specific CQAs not identified Effects of scale -Highly predictable-data across different scales can be projected. -Predictable-data across scales can be projected -Unpredictable-Scale impact
Slide 17 © PharmOut 2014 How many PPQ batches? Step 2: Risk Assessment of Control Strategy Step 3: Determine Overall Residual Risk Step 4: Translate Overall Residual Risk into # of PPQ Batches Stage 2 Activities Prepare PPQ Batches Compare results to Acceptance Criteria Risk Level Acceptable Step 1: Risk Assessment of Product Knowledge & Process Understanding Stage 1 Activities Assessments of Product Knowledge and Process Understanding
Slide 18 © PharmOut 2014 Step 2: Risk Assessment of Control Strategy • How the specifications were developed. Raw Materials Specifications • How easily the requirements for the process are accommodated by the manufacturing equipment. Equipment Capability vs. Process Requirements • How consistently the process has performed historically and during development studies. Experience with Process Performance • How the process is monitored and variability is detected Monitoring capability & detectability
Slide 19 © PharmOut 2014 Control Strategy - Risk Ranking Control Strategy Factor Source of Potential Variability and/or Uncertainty Relative Risk Ranking Characteristics of ranking assignments Low Risk Medium Risk High Risk Raw Material Specifications -Different suppliers; different manufacturing processes, -Material attributes test method -Different batches -Basis for material specification -Specification wider than experience -Specifications of material attributes impacting product quality based on development data -Limited justification of specifications of material attributes -Specifications are not justified. -Compendial or supplier limits accepted without further investigation
Slide 20 © PharmOut 2014 Control Strategy - Risk Ranking Control Strategy Factor Source of Potential Variability and/or Uncertainty Relative Risk Ranking Characteristics of ranking assignments Low Risk Medium Risk High Risk Equipment Capability vs. -Capability of equipment to -Comparison of parameter control -Comparison of control ranges from -Comparison of parameter control Process Requirements -Control operating parameters within acceptable ranges -Ranges from equipment qualification with process requirements indicates all parameters are well within equipment control capabilities and supported by qualification data -Equipment qualification with process requirements indicates marginal capability to meet requirements for a limited number of process parameters -Ranges from equipment qualification with process requirements indicates a significant number of parameters are similar to equipment control capabilities
Slide 21 © PharmOut 2014 Control Strategy - Risk Ranking Control Strategy Factor Source of Potential Variability and/or Uncertainty Relative Risk Ranking Characteristics of ranking assignments Low Risk Medium Risk High Risk Experience with process performance to date -Variation observed -Scaling effects Consistency of past performance -Underlying cause(s) for variation is understood & addressed (or variation not observed during manufacture) -Impact of scale is well understood -Process has consistently performed as expected -Variation is managed empirically, but underlying causes are not well understood -Some understanding of scaling issues -Minor departures from expected results that were investigated and satisfactorily explained -Variation has been observed, but has not been successfully managed -Impact of scale changes has not been explored -Unexplained failure has been experienced Monitoring capability & detectability -Ability of monitoring tools & methods to detect variation -Attributes measured in real time at a sensitivity where performance variability is likely to be observed -Attributes measured off-line (after batch completion) at a sensitivity where performance is likely to be observed -Attribute measurement accuracy is inadequate
Slide 22 © PharmOut 2014 Stage 2 Step 2: Risk Assessment of Control Strategy Step 3: Determine Overall Residual Risk Step 4: Translate Overall Residual Risk into # of PPQ Batches Stage 1 Activities Assessments of Product Knowledge and Process Understanding Stage 2 Activities Prepare PPQ Batches Compare results to Acceptance Criteria Risk Level Acceptable Step 1: Risk Assessment of Product Knowledge & Process Understanding
Slide 23 © PharmOut 2014 Step 3: Determine overall residual risk The residual risk level reflects the confidence in performance of the commercial process: Residual Risk Level Description Severe (5) Multiple factors have high risk ratings High (4) Few factors have high risk ratings or all have medium risk rating Moderate (3) Medium risk level for multiple factors or high risk level for one factor Low (2) Medium risk level for a few factors, the others are low risk Minimal (1) Low risk level for all factors
Slide 24 © PharmOut 2014 How many PPQ batches? Step 2: Risk Assessment of Control Strategy Step 3: Determine Overall Residual Risk Step 4: Translate Overall Residual Risk into # of PPQ Batches Stage 1 Assess Stage 2 Activities Prepare PPQ Batches Compare results to Acceptance Criteria Risk Level Acceptable Step 1: Risk Assessment of Product Knowledge & Process Understanding
Slide 25 © PharmOut 2014 Step 4: Translate overall residual risk into the number of PV Batches 1. Based on rationales and experience 2. Target Process Confidence and Target Process Capability • Statistical-includes measures of variability & confidence level 3. Expected Coverage • Statistical-includes measure of probability of batch success rate Note: Other approaches may be appropriate
Slide 26 © PharmOut 2014 How many PV batches? Approach 1: Rationales and experience Approach 2: Target process confidence & target process capability Step 4: Translate Overall Residual Risk into # of PPQ Batches 2 Approaches to Translate Overall Residual Risk into # of PV Batches
Slide 27 © PharmOut 2014 Approach 1: Rationales and Experience Residual Risk Level Number of Batches Rationale Severe (5) Not Ready for PV Encourage additional development to reduce risk level High (4) 10 High # of consecutive successful batches unlikely if controls are not adequate Moderate (3) 5 Increased residual risk addressed by preparing 2 additional PV batches to provide further demonstration of process consistency Low (2) 3 Knowledge & Control Strategy regarded as sufficient. 3 PPQ batches has historically been appropriate for demonstrating process consistency for many low-risk processes Minimal (1) 1-2 Minimal residual risk with less than 3 PPQ batches required, e.g. for verifying specific controls associated with a well-understood change to a process
Slide 28 © PharmOut 2014 Approach 2: Target process confidence & target process capability • Process Capability (CpK) is used as a measure of the capability of the process to consistently meet the quality requirements • Assumption: CpK ≥1 as a starting point for assessing the capability of a process undergoing validation
Slide 29 © PharmOut 2014 Approach 2: Target process confidence & target process capability • Used as a measure for level of confidence needed in the CpK and thereby as a degree of assurance • High level of confidence in the CpK can be built only with time and experience (during Stage 3) • Residual Risk Level used to define the confidence needed at completion of Stage 2.
Slide 30 © PharmOut 2014 Approach 2: Target process confidence & target process capability Residual Risk Level Target Confidence Comments Severe (5) N/A Major gaps in knowledge & understanding. Additional effort on product/process/control strategy development may be necessary. High confidence level needed to provide high degree of assurance. High (4) 97% Moderate (3) 95% Target confidence levels designed to provide reasonable assurance of process capability. Higher confidence levels would be achieved during Stage 3. Low (2) 90% Minimal (1) N/A High “confidence” based on existing understanding and capability of control strategy. Does not require additional assurance during PV beyond demonstration that commercial systems and procedures are appropriate.
Slide 31 © PharmOut 2014 Approach 2: Target process confidence & target process capability Residual Risk Level Min # of batches Target Confidence for CpK 1.0 Acceptance Criteria Readily Pass Calculated CpK Marginally Pass Calculated CpK Fail Calculated CpK Severe (5) Not Ready for PPQ N/A High (4) 11 97% ≥ 1.6 ≥ 1.0 and < 1.6 < 1.0 Moderate (3) 8 95% Low (2) 5 90% Minimal (1) 1-3 N/A • Based on a Target CpK of 1.0 and an actual CpK of 1.6. • May include clinical manufacture, demonstration, or other at-scale lots. Assumes process will be under statistical control & data will show normal distribution.
Slide 32 © PharmOut 2014 Approach 2: Target process confidence & target process capability PPQ Outcome Pass / Fail Other Considerations Impact on Initial CPV Sampling Approach* Readily Pass calculated CpK Pass N/A Supports Stage 3 routine sampling Marginally Pass calculated CpK Pass All input/output parameters within range Consider enhanced monitoring for CQA’s not meeting “Readily Pass” Fail calculated CpK Investigate -Parameter values -Intra-lot CpK -Probability of detection -Process improvement options Consider enhanced monitoring; May include some testing beyond PPQ. *PPQ outcome is one consideration in establishing CPV Plan
Slide 33 © PharmOut 2014 This session Using Risk to determine no of batches Risk vs criticality
Slide 34 © PharmOut 2014 FMEA - recap • Study the Failure Mode and Effect Analysis • It involves reviewing as many components, assemblies, and subsystems as possible to identify failure modes, and their causes and effects.
Slide 35 © PharmOut 2014 Ishikawa – Cause and Effect Diagram
Slide 36 © PharmOut 2014 Quality Risk Management (QRM) • This session will take a step back and look at the basics • We will ponder some topics: • Is the “Criticality Assessment” a “Variability Assessment” when discussing CQAs/CPPs for Qualification & Validation activities? • Do we throw out our innate understanding of the hazard because we are “FMEA” driven? FMEA does not help identify sources of variation
Slide 37 © PharmOut 2014 ICH Q9 Quality Risk Management (& Annex 20 of PIC/S PE 009-8) • ICH Q9 explains the “What” of QRM [10 pages] • Annex I of ICH Q9 provides concepts and ideas on the “How to”-formal and informal [4 pages] • Annex II of ICH Q9 details the potential “Where” of QRM [5 pages] • A “roadmap” is presented to us within the document, but do we follow it for Qualification & Validation activities? • For example, do we make use of QRM tools other than FMEA (or FMECA) effectively?
Slide 38 © PharmOut 2014 Quality Risk Management (QRM) • Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm • Harm: Damage to health, including the damage that can occur from loss of product quality or availability. • Severity: A measure of the possible consequences of a hazard. Begin the QRM Process Risk Identification Risk Analysis Risk Evaluation Risk Reduction Risk Acceptance Risk Assessment Risk Control Output of the QRM Process Review Events Risk Review QRM Tools Risk Communication
Slide 39 © PharmOut 2014 Quality Risk Management (QRM) Wet Floor (Hazard: The potential source of harm) Broken Leg (Harm: Damage to health, including the damage that can occur from loss of product quality or availability) Severity: A measure of the possible consequences of a hazard. Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm
Slide 41 © PharmOut 2014 Deductive vs Inductive Reasoning Destroyed my car. How did this happen? Intoxicated? What will happen if I drive? Inductive (forward logic) Deductive ? FMEA PHA FTA STA C&E Analysis
Slide 42 © PharmOut 2014 Inductive Reasoning Outcome Hypothesis Observation Confirmation Risk Identification Risk Analysis Risk Evaluation Risk Reduction Risk Acceptance “Top-down" “Think up” Failures! More Proactive?
Slide 43 © PharmOut 2014 Deductive Reasoning Theory Tentative Hypothesis Pattern Observation Risk Identification Risk Analysis Risk Evaluation Risk Reduction Risk Acceptance “Bottom-up" “Narrow down” Failure! More Reactive?
Slide 44 © PharmOut 2014 Inductive vs Deductive QRM QRM Tool Inductive Deductive “Complexity” FMEA Yes No Medium FMECA Yes No Medium FTA No Yes High HACCP Yes Yes Low HAZOP Yes No Medium PHA Yes No Low Risk Ranking and Filtering Yes Yes Low Supporting Statistical Tools Yes Yes Low
Slide 45 © PharmOut 2014 Appendix I: Risk Management Methods & Tools • General overview-references some primary tools “It is important to note that no one tool or set of tools is applicable to every situation in which a QRM procedure is used” FMEA FMECA FTA HACCP HAZOP PHA Risk Ranking & Filtering Supporting Stats Tools
Slide 46 © PharmOut 2014 Appendix I: Risk Management Methods & Tools QRM Tools Input Process Output FMEA Relies on product & process understanding. Manageable process steps. Once potential failure modes are established, risk reduction can be used to eliminate, contain, reduce or control the potential failures. Summarises modes of failure, factors causing these failures and the likely effects of these failures. FMECA Relies on product & process understanding. Manageable process steps. Once potential failure modes are established, risk reduction can be used to eliminate, contain, reduce or control the potential failures. 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. FTA System (or subsystem) failures Evaluates system (or subsystem) failures one at a time but can combine multiple causes of failure by identifying causal chains. The output of an FTA includes a visual representation of failure modes.
Slide 47 © PharmOut 2014 Failure Mode Effects Analysis (FMEA) Item or process Step Potential Failure Mode Potential Effect(s) of Failure Severity Potential Cause(s) Occurrence Current Controls Detection RPN Recommended Action Responsibility & Target Date Action Taken Severity Occurrence Detection RPN FMECA: Extended to incorporate an investigation of the degree of severity of the consequences, their respective probabilities of occurrence and their detectability
Slide 48 © PharmOut 2014 Appendix I: Risk Management Methods & Tools QRM Tools Input Process Output HACCP Product and process understanding. It is a structured approach that applies technical & scientific principles to analyze, evaluate, prevent, and control the risk or adverse consequence(s) of hazard(s) Risk management information that facilitates monitoring of critical points not only in the manufacturing process but also in other life cycle phases. HAZOP All processes & safety hazards. It is a systematic brainstorming technique for identifying hazards using so-called “guide- words”. As is the case with HACCP, the output of a HAZOP analysis is a list of critical operations for risk management. PHA Product, process and facility design information 1) Identification, 2) Evaluation 3) Ranking, and 4) Remediation Typically, hazards identified in the PHA are further assessed with other risk management tools such as those in this section.
Slide 49 © PharmOut 2014 Preliminary Hazard Analysis (PHA) • Early in the development: little information on design details or operating procedures will often be a precursor to further studies • For product, process and facility design • Further assessed with other risk management tools Hazards Arising from Product Design Hazard Investigation/ Controls Severity (S) Frequency (F) Impact (SxF)
Slide 50 © PharmOut 2014 Appendix I: Risk Management Methods & Tools QRM Tools Input Process Output Risk Ranking and Filtering Risk ranking and filtering can be used to prioritize manufacturing sites for inspection/audit by regulators or industry. Forms 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. 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. Supporting Statistical Tools Statistical data They can enable effective data assessment, aid in determining the significance of the data set(s), and facilitate more reliable decision making. Control Charts, Design of Experiments (DOE), Histograms, Pareto Charts, Process Capability Analysis
Slide 51 © PharmOut 2014 Appendix II: Potential Applications for QRM In II.1: Integrated Quality Management • To interpret monitoring data (e.g., to support an assessment of the appropriateness of revalidation or changes in sampling). • To determine appropriate actions preceding the implementation of a change, e.g., additional testing, (re)qualification, (re)validation or communication with regulators.
Slide 52 © PharmOut 2014 Appendix II: Potential Applications for QRM In II.4: Facilities, Systems & Equipment • To determine the scope and extent of qualification of facilities, buildings, and production equipment and/or laboratory instruments (including proper calibration methods). • To determine acceptable (specified) cleaning validation limits.
Slide 53 © PharmOut 2014 Appendix II: Potential Applications for QRM In II.4: Facilities, Systems & Equipment To select the design of computer hardware and software (e.g., modular, structured, fault tolerance); To determine the extent of validation, e.g., • identification of critical performance parameters; selection of the requirements and design; • code review; • the extent of testing and test methods; • reliability of electronic records and signatures.
Slide 54 © PharmOut 2014 Appendix II: Potential Applications for QRM II.6 Production • To identify the scope and extent of verification, qualification and validation activities (e.g., analytical methods, processes, equipment and cleaning methods; • To determine the extent for follow-up activities (e.g., sampling, monitoring and re-validation); • To distinguish between critical and non-critical process steps to facilitate design of a validation study.
Slide 55 © PharmOut 2014 Uses in Qualification & Validation QRM Tools Tools Uses in Q&V FMEA All Q&V Stages-prioritize potential risks and monitor the effectiveness of risk control activities. FMECA All Stages-Prioritize potential risks and monitor the effectiveness of risk control activities. Understand the impact of detectability FTA Establish the pathway to the root cause of the failure during Q&V. Is useful both for risk assessment and in developing monitoring programs as an output of Q&V. HACCP Used to identify and manage risks associated with physical, chemical and biological hazards (including microbiological contamination). HAZOP This facilitates regular monitoring of critical points in the manufacturing process. Used early in the design stage. Q&V input. PHA 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. Useful “first cut” for Q&V. Risk Ranking and Filtering Risk ranking is useful when management needs to evaluate both quantitatively-assessed and qualitatively-assessed risks within the same organizational framework. Stats Tools They can enable effective data assessment throughout Q&V activities
Slide 56 © PharmOut 2014 QRM vs Impact Assessment Example “Top Down” Critical Quality Attributes Critical Process Parameters System Subsystem Component End End Product carryover exceeds acceptance criteria Cleaning Agent Concentration CIP System Chemical Addition Chemical Feed Pump “Bottom Up” From ISPE GPG Applied Risk Management for C&Q
Slide 57 © PharmOut 2014 QRM vs Impact Assessment Characteristics Impact Assessment (Baseline® Guide 5) Formal Risk Assessment “Top Down” or “Bottom Up” “Bottom Up” “Top Down” Ability to identify specific process risks Low High Ability to identify specific Critical Aspects Low High Ability to prioritise Qualification efforts Medium High Cost in time and resources Medium High Need for SMEs experienced in the tool to be used Low High Acceptability to regulators Medium High Usefulness as “lifecycle” document in future Low High From ISPE GPG Applied Risk Management for C&Q
Slide 58 © PharmOut 2014 “Criticality” in Annex 15 • “It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations.” • “The protocol should specify critical steps and acceptance criteria.” • “Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment.” • “Risk analysis: Method to assess and characterise the critical parameters in the functionality of an equipment or process.”
Slide 59 © PharmOut 2014 Going from QTPP to CQA • We assume that during product development the clinicians and toxicologists have established that these parameters are high risk to the patient. • So we are looking at reducing the variability of these attributes.
Slide 60 © PharmOut 2014 Connecting a CQA to a CPP • The manufacturer during product development and based on prior product and process knowledge establishes that these process parameters have a high impact on variability. • “Validation” looks at ways to provide confidence that the variability is controlled.
Slide 65 © PharmOut 2014 Ishikawa – Cause and Effect Diagram
Slide 66 © PharmOut 2014 The PharmOut “STIC-man”! Summary Table from Ishikawa Criticality
Slide 67 © PharmOut 2014 Activity 3: QRM Please complete the Blue Sheets as a group and return them to us Please assign a Speaker/Scribe at each table If there are any questions, please ask!
Slide 68 © PharmOut 2014 Thank you for your time. Questions? Trevor Schoerie trevor.schoerie@pharmout.net Lead Consultant www.pharmout.net

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