Implementing Risk Management
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Implementing Risk Management

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Implementing Risk Management Implementing Risk Management Presentation Transcript

  • Implementing Risk Management in The Validation Process Gamal Amer, Ph. D. Principal Premier Compliance Services, Inc. © All rights reserved. Do not copy without permission. 1
  • Why Risk Management in Drug Manufacturing FDA Initiative August 2002Pharmaceutical CGMP for the 21st Century: A Risk-based ApproachA science and risk-based approach to product quality regulation incorporating an integrated quality system approach © All rights reserved. Do not copy without permission. 2
  • FDA Initiative August 2002 Its Objectives•  Allows Early adoption of new technology.•  Adoption of modern quality management techniques and implementation of the quality system approach.•  Focus on understanding the science & technology associated with what you are making.•  Priority to mitigating the highest risk elements of the manufacturing operation. © All rights reserved. Do not copy without permission. 3
  • FDA Initiative August 2002•  Take home: –  You must understand what you are doing. –  You must focus on critical areas (highest risk to product quality) of your operation. –  You should utilize automation and data collection to reduce risk associated with the operation and allow for continuous improvement. –  You must build the quality into your operation. © All rights reserved. Do not copy without permission. 4
  • Risk What Is Risk? What Causes It? Risk to Whom? Risk Manifestation? Risk Level?© All rights reserved. Do not copy without permission. 5
  • What Is Risk? The combination of the probability of occurrence of harm and the severity of that harm.**ICH Consensus Guideline; Q9 Quality Risk Management; June 2006 © All rights reserved. Do not copy without permission. 6
  • Risk•  Risk is always present in every endeavor .•  We as humans learn about it, recognize it subconsciously, and accept a certain level of risk on a daily basis.•  We always take steps in daily life to mitigate the risk associated with our activities. © All rights reserved. Do not copy without permission. 7
  • Risk in Drug ProductDevelopment & Manufacturing © All rights reserved. Do not copy without permission. 8
  • Quality Events Which May Cause Increased Risk•  A problem occurs during clinical trials (patient complains/suffers)•  Un-controllable or un-expected process variability•  A deviation occurs during the manufacturing•  Analytical result is not what was expected•  A piece of equipment is identified as malfunctioning after the operation is complete. © All rights reserved. Do not copy without permission. 9
  • These Events Increase:•  Risk to the patient/public•  Risk to the product•  Risk to the personnel•  Risk to the company © All rights reserved. Do not copy without permission. 10
  • Risk to whom?•  We are concerned here with the risk to the quality of the product and hence to the patient.•  We will focus on the risk in the product lifecycle in general and in the manufacture lifecycle in particular.•  We will focus on validation, GMP and quality systems as used to mitigate risk. © All rights reserved. Do not copy without permission. 11
  • Higher Risk Manufacturing Operations•  Aseptic Processing (Contamination of product)•  Dealing with potent compounds (danger to patient from incorrect formulation and to workers from potential exposure)•  Solid dosage (Cross contamination)•  Labeling (Incorrect labeling) © All rights reserved. Do not copy without permission. 12
  • ICH Q9 Quality Risk Management•  Outlines Quality Risk Management Principles for Product Lifecycle.•  Phases of QRM include risk assessment, risk control, risk review, risk communication.•  Defines Risk and How to Measure it.•  Outlines the principle of focusing on the critical aspects of the drug manufacturing based on the level of risk.•  Use of change management to reduce risk. © All rights reserved. Do not copy without permission. 13
  • ICH Q9 Quality Risk Management•  The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.•  The level and extent of actions to be taken to eliminate or minimize actual or potential risk must be appropriate to the magnitude of the problem and commensurate with the level of risk anticipated. (ICH Q9) © All rights reserved. Do not copy without permission. 14
  • Defining Level of RiskFunction of: –  Severity –  Frequency –  Detectability•  These three factors determine the numerical Risk Priority Number (RPN)•  Qualitative risk (low, medium, and high) © All rights reserved. Do not copy without permission. 15
  • Risk Level Factors: Severity•  What are the consequences of the quality event (non-conformance or deviation)?•  How deleterious is that potential variability, failure, or deviation?•  How high is the risk to the patient’s well being? Would it affect or delay his/her treatment? © All rights reserved. Do not copy without permission. 16
  • Risk Level Factors: Frequency•  What are the probability of the occurrence of the failure/deviation?•  Were attempts made to reduce such frequency in the past? How successful?•  Review process/operation/design history. © All rights reserved. Do not copy without permission. 17
  • Risk Level Factors: Detectability•  What is the probability of the variability, failure, or deviation being detected?•  Can the effect/result of the failure/deviation be readily measured/seen? © All rights reserved. Do not copy without permission. 18
  • Developing Risk Priority Number RPN•  Severity: –  Could result in the manufacture of a product, which may cause death or serious harm requiring intervention(3) –  ……product that may cause or contribute to a patient discomfort or an insignificant delay or interruption in treatment. (2) –  ….. product that will NOT cause injury or discomfort, or delay/interruption in treatment. (1) © All rights reserved. Do not copy without permission. 19
  • Developing Risk Priority Number RPN•  Frequency: –  Would definitely occur, is known to have occurred in the past, expected to reoccur if no action is taken to correct or prevent the problem. (3) –  Unlikely to occur or not expected to reoccur, but it is possible. (2) –  Will not occur or is highly unlikely to.(1) © All rights reserved. Do not copy without permission. 20
  • Developing Risk Priority Number RPN•  Detactability: –  Consequences of the events are not detectable or readily obvious (3) –  Consequences of the event are not obvious but, there is a good possibility that, it will be detected.(2) –  Consequences of the event are detectable (1) © All rights reserved. Do not copy without permission. 21
  • Developing Risk Priority Number RPNRisk Priority Number (RPN)= Severity X Frequency X DetectabilityRPN= 1-4 Low RiskRPN= 5-11 Medium RiskRPN= 12-27 High RiskThese ranges could vary based on experience © All rights reserved. Do not copy without permission. 22
  • Mitigating RiskThe level and extent of actions to be takento eliminate or minimize actual or potentialrisk must be appropriate to the magnitudeof the problem and commensurate with thelevel of risk anticipated. (ICH Q9) © All rights reserved. Do not copy without permission. 23
  • Risk AssessmentTylenol scare of the early 1980s:Several death due to tampering withproduct capsules. The event happenedtwice. Consumer unable to recognizedcapsules were tampered with. © All rights reserved. Do not copy without permission. 24
  • Using The Risk Assessment FormSeverity: Highest –Result in death (3)Frequency: happened twice, does nothappen often, will surely happen again (3)Detactability: Difficult to detect a capsulethat was tampered with (3)RPN: 27 © All rights reserved. Do not copy without permission. 25
  • Using The Risk Assessment FormCorrective Action: Immediate recallInvestigation: Unable to protect capsulesPreventive action: - Eliminate the use of capsules. - Develop Tamper evident packages © All rights reserved. Do not copy without permission. 26
  • Interactive Exercise © All rights reserved. Do not copy without permission. 27
  • Risk Causing Scenarios:If any of the attendees has an example of a risk causing scenario we can address it as a group.1. In a drug release test, the HPLC instrument has a completefailure while analyzing the drug sample for the impuritiesprofile. The drug has a limited shelf life andmust be released within one day of production. The test itselfrequires 20 hours to perform (sample prep and analysis). Theimpurities profile is the most critical release test.2. In the coating of an over the counter analgesic, the color ofthe coating material was affected by the temperature of thecoating pan and was several shades darker. The coating issugar based food coloring. It is well understood that the foodcoloring does not have toxic effects/degradents. (Shouldoverheating occur; did it affect the drug substance?). © All rights reserved. Do not copy without permission. 28
  • Risk Causing Scenarios:3. In the manufacture of an API at the completion of acampaign, consisting of 6 batches, the catalyst bed wasopened to introduce fresh material in preparation for the nextcampaign. Upon opening the catalyst bed it was determinedthat the bed is contaminated with an unknown solid material.Further investigation indicated that the contaminant is inertand insoluble.4. Patients suffer from heart problem due to over dosage ofactive in product tablets ingested (tablets contain largeramount of active than indicated). This is reported by doctorsas an adverse event. © All rights reserved. Do not copy without permission. 29
  • Process Validation: General Principles and Practices•  Guidance to industry issued by the FDA in January 24, 2011.•  Outlines a life cycle approach to validation.•  Inline with the principles advanced in ICH Q8, ICH Q9, ICH Q10 and in ASTM E2500.•  Defines PROCESS VALIDATION as the collection and evaluation of data, from the process design stage throughout commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. © All rights reserved. Do not copy without permission. 30
  • FDA Guidance: Process Validation: General Principles and Practices•  Replaces the guidance issued in 1987•  “Quality of the product cannot be assured by simply inspecting or testing in-process and finished products.” It must be built into the product-process a-priori.•  “Focusing exclusively on the qualification effort without understanding the process and ensuring the process is maintained in a state of control may not lead to adequate assurance of quality.” © All rights reserved. Do not copy without permission. 31
  • FDA Guidance To Industry January 2011•  Three Stages of Process Validation –  Process Design Stage (process is defined based on development and scale-up) –  Process Qualification Stage (Design is confirmed as being capable of reproducible production) –  Continued Verification and improvement (Continuously gaining assurance the process remains in a state of control) © All rights reserved. Do not copy without permission. 32
  • Stage 1: Process Design•  Understanding the science•  Understanding the risk•  Building Quality into the process•  Establishing Control Strategy © All rights reserved. Do not copy without permission. 33
  • Stage 2: Implementation and Process Qualification•  Implement the process and Facility•  Qualification of utilities and equipment•  The Process Performance Qualification (PPQ) protocol•  Protocol execution and report © All rights reserved. Do not copy without permission. 34
  • Stage 3: Continued Process Verification•  Monitoring appropriate parameters to ensure process in a validated state of control.•  Use CAPA, PAT and Change control as well as data collected in monitoring to continually improve the process.•  Proper maintenance of the facility, utilities, and process equipment © All rights reserved. Do not copy without permission. 35
  • Risk Assessment in Process Validation•  Risk analysis is used in all three stages of Process Validation.•  Always use risk-based approaches to justify decisions. However such use should be scientifically sound with the goal of achieving and maintaining a high level of product quality. © All rights reserved. Do not copy without permission. 36
  • Risk Assessment in Process Validation•  In stage 1 risk analysis is used in conjunction with QbD to develop a robust design and reduce variability.•  In stage 2 risk analysis is used to prioritize your activities and focus the effort on critical systems.•  In stage 3 it is used in conjunction with a CAPA program to ensure the process remains in a state of control. © All rights reserved. Do not copy without permission. 37
  • Stage 2 Process QualificationGoal: Evaluate the design developed in stage1 to determine if it is capable of reproducible commercial manufacturing and performs as expected. Must follow CGMP-Compliant procedures © All rights reserved. Do not copy without permission.
  • Stage 2 of Guidance Stipulates•  Facility Design and Utilities & Equipment Qualification: –  Must properly design and commission facility prior to the PPQ (Process Performance Qualification) –  Qualification of utilities and equipment (activities to demonstrate equipment are suitable for intended use) •  Demonstrate proper selection of material and design •  Demonstrate proper construction and installation •  Demonstrate that equipment and utilities operate in accordance with the process requirements (include appropriate challenges to represent normal operation) –  Qualification activity must be documented and summarized in a report with appropriate conclusions © All rights reserved. Do not copy without permission. 39
  • Stage 2 of Guidance Stipulates•  Qualification Plan For Utilities –  Qualification of utilities and equipment can be covered under individual plans or under an overall plan. –  Plan should consider requirements of use and risk management used to prioritize and define extent of activities. –  Plan should define: •  Studies and tests to be conducted •  The criteria to assess outcome of studies •  Timing for qualification •  Responsibilities for conducting the effort •  Procedure for documenting and approving the qualification –  Outline firm’s criteria for evaluating changes © All rights reserved. Do not copy without permission. 40
  • Stage 2 of Guidance Stipulates•  Process Performance Qualification Approach: –  PPQ should combine qualified facility, utilities, and equipment with trained personnel to confirm the commercial manufacturing performs as expected. –  PPQ must be completed before commercial distribution of drug. –  PPQ should be based on science and technical understanding. –  Employ statistical metrics to achieve adequate assurance through data analysis. –  PPQ should have additional (when compared to normal production) sampling, monitoring, and analysis –  The concept of ongoing PPQ to determine usable lifetime of resin columns and the like. –  If using PAT, a different approach to PQ maybe warranted: •  Qualification to focus on measurement and control loop. •  Establish that the process is reproducible and will deliver quality product. © All rights reserved. Do not copy without permission. 41
  • Stage 2 of Guidance Stipulates•  Process Performance Qualification Protocol: –  Written Protocol delineating manufacturing conditions, controls, sampling, testing, and expected outcome. –  PQ should discuss manufacturing conditions, operating parameters, limits, and components. –  PQ should discuss the data to be collected and when and how it will be evaluated. –  PQ establishes the tests to be performed and acceptance criteria. –  PQ should detail the sampling plan (e.g. Number of samples and frequency of sampling). © All rights reserved. Do not copy without permission. 42
  • Stage 2 of Guidance Stipulates•  Process Performance Qualification Protocol (cont): –  Description of statistical methods to be used and how to address deviations and non-conforming data. –  Confirm that facility and utility qualification have been successfully completed. –  Confirm personnel training and qualifications. –  Verification of material sources (components and container/closures) –  Discuss status of analytical methods validation. –  Should be reviewed and approved by appropriate departments and Quality Unit. © All rights reserved. Do not copy without permission. 43
  • Stage 2 of Guidance Stipulates•  Protocol Execution and Report: –  Only execute approved protocol. –  Departures from the approved protocol to be justified and approved. –  Follow expected routine procedures for commercial process using personnel who will be responsible for manufacture. –  Report to be prepared in a timely manner, should include: •  Summary and analysis of data. •  Evaluation of unexpected results. •  Evaluate manufacturing non-conformances (deviations, OOS results, etc.). •  Description of corrective actions taken. •  A clear statement as to the process being fit for the intended use. •  Review and approval by appropriate departments and quality unit. © All rights reserved. Do not copy without permission. 44
  • What it all means?•  PPQ to confirm process design•  PPQ to confirm manufacturing process•  PPQ To be completed before manufacture and distribution•  Previous credible experience with similar products & processes can be considered•  Entire operating range need not be verified, only normal operation. © All rights reserved. Do not copy without permission. 45
  • Managing Risk Through Validation is Achieved By:•  Qualification of high risk portions of the facility and utilities.•  Qualification and verification of high risk portions within the process.•  Qualification of source of variability in the process.•  Focusing on portions of the process that have the greatest risk to product quality. © All rights reserved. Do not copy without permission. 46
  • Risk Assessment•  Based on forward looking analysis (what happens if this unit operation fails?).•  Based on the knowledge of the science associated with the operation/process.•  Defining the focus of the risk assessment, e.g. product quality vs. environmental spills (potential issues that cause environmental spills excluded).•  Divide the process into manageable subsystems.•  Historic information. © All rights reserved. Do not copy without permission. 47
  • Risk Assessment Form•  Page one: –  Product information –  Information regarding potential Risk associated with the system –  Description of the issue –  Description of the findings of any investigation –  Description of relevant historical information © All rights reserved. Do not copy without permission. 48
  • Risk Assessment Form•  Page two: –  Analysis of Severity –  Analysis of Frequency –  Analysis of Detectability•  Page three: –  Calculation of RPN –  Definition of action to be taken (commissioning, Installation and Operation qualification only, IOQ and Performance Qualification) © All rights reserved. Do not copy without permission. 49
  • Risk Assessment Form•  Actions to be taken: –  High RPN - Intolerable •  Understand causes and reason for risk •  Reduce or eliminate risk of further occurrence (re-design) if possible •  Complete qualification IOQ and PQ –  Medium RPN – Tolerable •  Evaluate event •  Determine if additional investigation is warranted •  Conduct reasonable and practical qualification (IOQ) –  Low RPN – Negligible •  No additional investigation •  Monitor through trend analysis for further occurrences •  Commissioning maybe sufficient. © All rights reserved. Do not copy without permission. 50
  • Use of Risk Assessment in Process Qualification © All rights reserved. Do not copy without permission. 51
  • Prioritizing the Qualification Effort•  Which systems should be included as part of the formal qualification effort and which does not have to be.•  Use of appropriate tools for risk analysis to list causes and effect (e.g. Failure Mode and Effect Analysis FMEA, Fault Tree Analysis, HAZOP, HACCP) © All rights reserved. Do not copy without permission. 52
  • InteractiveWhat to do for the following? © All rights reserved. Do not copy without permission. 53
  • Qualification of Facility/Utility Systems1.  HVAC in sterile processing facility.2.  Electric system in common production space.3.  Generator and Un-interruptable power supply in fermentation facility4.  Steam generation for power plant.5.  HVAC in for general laboratory © All rights reserved. Do not copy without permission. 54
  • Qualification of Facility/Utility Systems1.  Full qualification of HVAC system (issue contamination of sterile product, severity= 3, frequency =3, detectability=3, RPN=27)2.  Commissioning is sufficient based on severity due to malfunction(issue electric malfunction, Severity=?, Frequency=3, detectability=1 RPN=3-?) © All rights reserved. Do not copy without permission. 55
  • Qualification of Facility/Utility Systems3. IOQ and possibly PQ if fermentation is very expensive (Issue: Power interruption in fermenter for aerobic fermentation can result in fermentation failure (severity=2-3 depending on cost, Frequency=3, detectability=1, RPN=6-9)4. Commissioning sufficient (issue power loss if steam generation fails, important components have back-up, severity=1, frequency=3, detectability=1 RPN=3) © All rights reserved. Do not copy without permission. 56
  • Qualification of Facility/Utility Systems5. Commissioning sufficient (issue failureHVAC resulting in discomfort, severity=1,detectability=1, frequency=3 RPN=3) © All rights reserved. Do not copy without permission. 57
  • Qualification of Processing Equipment•  All equipment used in the process should be qualified (IOQ) at a minimum to: •  Demonstrate proper selection of material of construction and design •  Demonstrate proper construction and installation •  Demonstrate that equipment and utilities operate in accordance with the process requirements (include appropriate challenges to represent normal operation)•  Processing subsystems that can compromise the quality of the product must be fully qualified. © All rights reserved. Do not copy without permission. 58
  • Qualification of High-risk Subsystems•  Components of the process which could lead to variability should be tested to a higher level (PQ)•  Critical utility systems representing high risk, are to be full qualified (PQ); –  HVAC, WFI, Purified Water, Clean compressed air, etc.•  Critical utility/process systems must be fully qualified, e.g.: –  Autoclave, Incubators, Stability Chambers, Refrigerators and freezers, etc. © All rights reserved. Do not copy without permission. 59
  • Qualification of High-risk Subsystems•  Fermenter: poor cell growth, poor cell viability and contamination would result in low product titer and poor quality (S=3, F=3, D=2 RPN=12), Complete validation to show ability to provide reproducible results and adequacy of controls.•  UF Membrane installation: Leakage of product and product loss. Due to damaged unit installed or damaging the unit during installation. Test integrity after installation (S=2, F=2, D=1 RPN=4). No need to fully qualify, maybe referenced in fermenter protocol. Can be controlled procedurally during operation. © All rights reserved. Do not copy without permission. 60
  • Qualification of High-risk Subsystems•  What to do in cases where RPN suggest no need for full qualification?•  Perform secondary evaluation –  Regulatory commitments may necessitate qualification –  Industry expectations –  Experience with previous inspections –  Procedural requirements•  Example: Buffer preparation system; incorrect composition and incorrect conditions of preparation result in incorrect buffer pH and conductivity and possible chemical breakdown of components (S=2, F=2, D=1; RPN=4) Managed procedurally, but still qualified per industry practice. © All rights reserved. Do not copy without permission. 61
  • Process Performance Qualification•  The entire process is tested using, qualified and non-qualified systems, trained personnel and procedures based on a well designed protocols.•  Data is collected in larger amounts when compared to normal operation and statistically analyzed to ensure the process is fit for the intended use. © All rights reserved. Do not copy without permission. 62
  • Process Performance Qualification•  Parts of the process which are known to cause variability are monitored for variations within the batch and from batch to batch.•  You do not need to test the process limits, instead testing should of the expected normal operating range.•  Three runs and done is no longer the way to do it. © All rights reserved. Do not copy without permission. 63
  • Advantages of Applying Risk Based Validation•  Better understanding of the science of your operation and the risks associated with it.•  Only address necessary systems thus optimizing the effort.•  Focusing your resources on critical systems realizing considerable savings.•  Ensure that no critical system is missed during and after the qualification effort is complete.(through doing a formal risk analysis of the entire operation) © All rights reserved. Do not copy without permission. 64
  • Interactive•  Why? –  Full qualification for, stability chamber, autoclave, WFI, What else? –  Only IOQ for Dust collection systems, Transfer conveyor, distribution system for purchased gas, What else? –  Only commissioning for processing pumps, potable water system, What else? © All rights reserved. Do not copy without permission. 65