CAPA: A Risk Mitigating Quality System

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This presentation discusses risk in the context of CAPA, FDA requirements for risk-management, and risk level factors.

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CAPA: A Risk Mitigating Quality System

  1. 1. Corrective And Preventive Action CAPA: A Risk Mitigating Quality System Conducted by Gamal Amer, Ph.D. Principal Premier Compliance Services, Inc. © All rights reserved. Do not copy without permission. 1
  2. 2. FDA Initiative August 2002 Pharmaceutical 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
  3. 3. Mitigating RiskFDA Progress Reports discusses threeQA systems to mitigate risk:1. Process Analytical Technology (PAT)2. Corrective and Preventive Action (CAPA)3. Quality by Design (QbD) © All rights reserved. Do not copy without permission. 3
  4. 4. Risk What Is Risk? What Causes It? Risk to Whom? Risk Manifestation? Risk Level?© All rights reserved. Do not copy without permission. 4
  5. 5. Qu y ve s W cQuality Events Which May Cause y C use Increased Risk• A problem occurs during clinical trials (patient complains/suffers)• A deviation occurs during the manufacturing• A piece of equipment fails while the process i f i t f il hil th is engaged.• Analytical result is not what was expected © All rights reserved. Do not copy without permission. 5
  6. 6. Events P t ti ll I E t Potentially Increasing i Risk No negative q g quality event occurred, but: y• Patient complaints show a negative trend.• Operation drifting/trending towards action i d if i / di d i limit.• Analytical data trending towards unacceptable. © All rights reserved. Do not copy without permission. 6
  7. 7. These Events Pose:• Risk to the patient/public• Risk to the product• Risk to the personnel• Risk Ri k to the environement h i• Risk to the company © All rights reserved. Do not copy without permission. 7
  8. 8. What Is Risk? The combination of the probability of occurrence of harm and the severity of that harm.**Guidance for Industry; ICH Q9 Quality Risk Management; June 2006 © All rights reserved. Do not copy without permission. 8
  9. 9. What Is The Risk?• In Drug Application: – The pros and cons of the treatment• In Process Design: – Failure to recognize source of variability and how CPP affect CQA of product• In Process Qualification: – Failure to qualify a critical (high risk) portion of the process.• In Manufacturing: – Quality events occurring as the process is engaged © All rights reserved. Do not copy without permission. 9
  10. 10. Some Sources of Increased Risk in Manufacturing?• Processing Deviations and Non Conformance• A ti Processing Aseptic P i• Labeling Errors (Majority of drug recalls due to mislabeling)• Analytical and Measuring Errors• D li with potent compounds Dealing ith t t d• People Errors © All rights reserved. Do not copy without permission. 10
  11. 11. Defining Level of RiskFunction of:F i f – Severity –FFrequency – 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. 11
  12. 12. CAPA = Corrective Action / Preventive Action © All rights reserved. Do not copy without permission. 12
  13. 13. Risk Within the Context of CAPA System y• A non-conformance or deviation occurs or a potential p problem is identified.• These pose risk.• CAPA should define the risk, its level, and means to mitigate it. it• CAPA should then implement the actions to mitigate the risk and track to ensure closure.• M i to ensure action is effective and did not Monitor i i ff i d introduced new risk(s). © All rights reserved. Do not copy without permission. 13
  14. 14. Non-conformance and Deviation Non-Conformance: Failure to meet a specified requirement. p q Deviation: Failure to follow or implement an established requirement. Typically this term is used relevant to processes (as in a “process process deviation”). © All rights reserved. Do not copy without permission. 14
  15. 15. Risk Level Factors: Severity• What are the consequences of the non-conformance q or deviation?• How deleterious is that non-conformance or deviation to the consistent quality of the product?• How high is the risk to the patient’s well being? © All rights reserved. Do not copy without permission. 15
  16. 16. Risk Level Factors: Frequency• What are the probability of the reoccurrence of the non-conformance or deviation?• Were attempts made to reduce such frequency and how effective?• Review process history to determine. © All rights reserved. Do not copy without permission. 16
  17. 17. Risk Level Factors: Detectability• What is the probability of the non-conformance or deviation b i d d i i being detected? d?• Can the effect/result of the non-conformance or deviation be dil d i ti b readily measured/seen? d/ ? © All rights reserved. Do not copy without permission. 17
  18. 18. Change Control is an Important Component of CAPA © All rights reserved. Do not copy without permission. 18
  19. 19. Change Control: A Regulatory Imperative I i• Is a regulatory requirement• 211.68(b) Appropriate controls shall be exercised over computer or related systems to assure that p y changes....• 211.100 (a) ....written procedures, including any ( ) p , g y changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. © All rights reserved. Do not copy without permission. 19
  20. 20. • 211 160( ) change in such specifications, 211.160(a) h i h ifi ti standards, sampling plans, test procedures, or other laboratory control mechanisms shall be mechanisms, drafted by the appropriate organizational unit and reviewed and approved by the quality control unit.• Guidance to Industry on Process Validation: The qualification plan for the facility and utilities should identify 1) studies.... 2)Criteria to assess outcome...It should also include the firms requirements for the evaluation of changes. i t f th l ti f h © All rights reserved. Do not copy without permission. 20
  21. 21. • ICH Q7-API GMP (13) A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API.• A proposals f GMP relevant changes should Any l for l h h ld be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s). © All rights reserved. Do not copy without permission. 21
  22. 22. What is a Change Control System?It is a formal system which is designed not to prevent change, but rather document and control it. change it Its main purpose is to ensure that a system/process/operation is always in a GMP y p p y compliant and validated state, regardless of changes made to it. It is usually implemented using a procedure. © All rights reserved. Do not copy without permission. 22 22
  23. 23. What is a Change Control System? ICH Q9 – Quality Risk Management• T manage changes based on k To h b d knowledge and l d d information accumulated in pharmaceutical development and during manufacturing manufacturing.• To evaluate the impact of the changes on the availability of the final product. © All rights reserved. Do not copy without permission. 23 23
  24. 24. What is a Change Control System?• To evaluate the impact on product quality of changes to facility, equipment, material, facility equipment material manufacturing process or conducting technical transfers.• To determine appropriate actions preceding the implementation of a change, e.g., additional testing, (re)qualification, (re)validation, communication with regulators. © All rights reserved. Do not copy without permission. 24 24
  25. 25. The Compliance/Validation p Life Cycle - Compliant & Validated SystemChange Control Implement Change System Modified System © All rights reserved. Do not copy without permission. 25 25
  26. 26. Importance of Change Control• Not to prevent change. change• To control and document change.• Required by the regulations.• Identify GMP and validation implications. y p• Ascertain process remains in a state of control. control• Must be implemented using a procedure. © All rights reserved. Do not copy without permission. 26 26
  27. 27. Change Control procedureChange required GenerateChange Request No GMP Implement Change Implications? Maintenance End YesRequalification? No Implement Change Issue GMP Obtain Approval Revalidation? & Insure GMP Requirements Done Report Yes Requalify Obtain Change is Revalidate & Change is Issue Reports Approvals Permanent Permanent End © All rights reserved. Do not copy without permission. 27 27
  28. 28. CAPA: Mitigating RiskThe degree of corrective and preventiveaction taken to eliminate or minimize actualor potential nonconformities must beappropriate to the magnitude of the p pp p g problemand commensurate with the risksencountered. (ICH Q ) ( Q9) © All rights reserved. Do not copy without permission. 28
  29. 29. Risk Level and Appropriate Corrective Action Risk Level (RPN) Low Medium HighCorrective ActionNo Further Investigation ,No Corrective actionrequiredNo Further Investigation(Cause Evident),Corrective action requiredFurther Investigation (RootCause Analysis), Corrective y ),action required (Immediate;e.g.. Recall), Prevent Cause © All rights reserved. Do not copy without permission. 29
  30. 30. What Is CAPA?© All rights reserved. Do not copy without permission. 30
  31. 31. CAPA Is:• A quality based system• Uses Non-conformance, Deviations and/or an Expectation of such as input• Uses many of the quality systems in place as tools: – Historical Quality Issues and Audit Reports – Environmental and Process Monitoring Data – Product Complaints – Equipment Service & Maintenance Records – Process and scientific Knowledge – Operating Procedures and Methodology © All rights reserved. Do not copy without permission. 31
  32. 32. CAPA Uses:• Policies and procedures to in estigate proced res investigate quality problems.• Policies and procedures to identify and implement corrective and preventive actions. actions• A tracking mechanism to ensure investigation and proper corrective actions are conducted and implemented on a timely basis. © All rights reserved. Do not copy without permission. 32
  33. 33. CAPA Investigation• Investigate the cause of non-conformity or deviation as it relates to the product, processes, and the quality system. (reactive)• I Investigate potential risk of an expected or ti t t ti l i k f t d anticipated event. (proactive)• Depending on risk severity the investigation may severity, need to define the “Root Cause.”• Use tools such as HAZOP, HACCP, Failure Mode , , & Effect Analysis, Fault Tree Analysis, What If, etc. © All rights reserved. Do not copy without permission. 33
  34. 34. CAPA Identification• Identify the action needed to correct, reduce, or p prevent recurrence of nonconformance of product p and other quality problems.• Identify the action needed to correct and prevent recurrence of the deviation in the process.• Identify the action needed to prevent the potential occurrence of an anticipated quality event. © All rights reserved. Do not copy without permission. 34
  35. 35. Possible Corrective Actions• Design Changes*• Manufacturing Process Changes*• Removal of product from the market through recall• Operator Training• Labeling changes*• Patient education ________________________________________________________________________________* Keep in mind that making changes must be managed using change control in order to avoid introducing additional risk. © All rights reserved. Do not copy without permission. 35
  36. 36. Tracking CAPA Activities• What to track? – The quality event and timing for initiating an investigation – Timing for completing assessment – Timing for developing action plan – Timing for implementing all necessary actions (changes, training, document modification, etc.) – Timing for completing the necessary documentation – Completion of the actions and closure of the deviation or nonconformance © All rights reserved. Do not copy without permission. 36
  37. 37. Tracking CAPA Activities• How to track? – Manual Tracking • Too much paper • Very cumbersome and time consuming • Limited Access – Software Packages (Part 11 compliant) • Trackwise (MS Outlook) • Livelink (Lotus) © All rights reserved. Do not copy without permission. 37
  38. 38. Post CAPA Monitoring• Ensures actions were effective in mitigating the risk.• Ensure actions were effective in correcting/preventive the problem.• Ensures no additional risks were introduced due to the actions taken.• Required as part of GMP compliance and process validation (FDA Guidance 1/2011). © All rights reserved. Do not copy without permission. 38
  39. 39. Typical CAPA Overall Approach Quality Event History Identify Risk Risk Ri k Acceptance Document MonitoringComplaints Track& Analyze Risk Risk Reduction Monitor Science & KnowledgeProcedures, Service Risk Communicate& Maintenance Evaluate Risk Elimination/ Assign A i RPN prevention Review Risk Assessment/ Identify & Document, Track, Investigate Monitor & Implement Actions l A i Communicate © All rights reserved. Do not copy without permission. 39
  40. 40. System Components• D i ti reporting and i Deviation ti d investigation procedure. ti ti d• Rework Procedures.• M i Maintenance records, hi d historical Data, quality audit i lD li di results, etc.• P Process and environmental monitoring programs. d i t l it i• Change Control Procedure.• Ri k Analysis Procedures such as HAZOP, Risk A l i P d h HAZOP HACCP, Fault Tree Analysis, etc. © All rights reserved. Do not copy without permission. 40
  41. 41. CAPASteps to Be Taken© All rights reserved. Do not copy without permission. 41
  42. 42. Label and Segregate Non- conforming Product• Ensure nonconforming product is properly labeled (for example, HOLD, REJECT, example HOLD REJECT QUARANTINE).• E Ensure suspect or non-conforming product t f i d t is properly labeled and segregated (not used) t prevent further use pending d) to t f th di disposition. © All rights reserved. Do not copy without permission. 42
  43. 43. Document The Issue• Record nonconformance on a Nonconforming Materials Report. g p• Record Deviation on a Deviation Reporting Form. Form• Document all studies and decisions made during the investigation of the quality event. event © All rights reserved. Do not copy without permission. 43
  44. 44. Segregate Material & Equipment• A Assure that suspect materials (non-product) i h i l ( d ) is segregated and labeled.• Assure all suspect lots batches units, materials lots, batches, units materials, etc are identified and segregated.• Assure that the segregation (who, what, where, g g ( , , , when, how) is documented on the nonconformance report.• T and lock all equipment and parts of the Tag d l k ll i d f h process which maybe suspect. © All rights reserved. Do not copy without permission. 44
  45. 45. Evaluate• Review the event, the circumstances surrounding the event.• Document relevant details as part of the nonconformance or deviation report. report• Risk to quality should be linked to protecting the patient.• Use RPN to help determine need for in-depth investigation and Corrective/Preventive Action (in other words: the effort, formality and documentation should be commensurate with the level of risk and be based on science*).__________________________________________________________________________*Guidance for Industry; ICH Q9 Quality Risk Management; June 2006 © All rights reserved. Do not copy without permission. 45
  46. 46. Risk Level and Appropriate Corrective Action Risk Level (RPN) Low Medium HighCorrective ActionFurther Investigation (RootCause Analysis), Correctiveaction required (Immediate;e.g.. Re ll) P e e t C ee Recall), Prevent CauseNo Further Investigation(Cause Evident),Corrective action requiredNo Further Investigation , NoCorrective action required © All rights reserved. Do not copy without permission. 46
  47. 47. Take Action• M k necessary changes to reduce risk or Make h d ik eliminate it.• Invoke Change Control. Control• Track to ensure CAPA closure in a timely fashion.• Evaluate the actions to ensure they were effective in mitigating the risk as intended.• Monitor the process to ensure it has not been p negatively affected by changes and that no additional or different risks were introduced. © All rights reserved. Do not copy without permission. 47
  48. 48. Benefits of a Robust CAPA System• Fulfills the promise of continuous improvement• Leads to better customer satisfaction and less risk to the public. h bli• Better use of resources through a structured QA system. system• Facilitate better and more informed decisions by manufacturers.• Makes good business and financial sense.• Increasing your compliance q gy p quotient. © All rights reserved. Do not copy without permission. 48
  49. 49. Summary y• CAPA is a regulatory requirement which makes business sense.• CAPA is a risk mitigating approach, which fulfills the promise of continuous improvement improvement.• Non-conformances, deviations or anticipated quality events are input to the CAPA program.• All aspects of the CAPA program should be thoroughly documented.• Risk level assessment, as part of CAPA: p provides the means for rationalizing the scope and g p extent of investigation and/or corrective action necessary. helps management assign resources to tasks providing the most value and having the biggest impact on al e ha ing quality and customer satisfaction.• Tracking, reviewing, and monitoring CAPA related activities is an important aspect of the program. © All rights reserved. Do not copy without permission. 49

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