Deviation, OOS, Complaint Investigation_GMP_Dr. Amsavel

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Deviation, OOS Complaint Investigation and
CAPA
Dr. A. Amsavel, M.Sc., B.Ed., Ph.D.
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OVERVIEW

• Definition
• Requirement
• Deviation, OOS and reporting
• Investigation
• RCA
• Investigative tools Why Why , Cause Effect
  and FTA
• Human error
• CAPA
• Implementation
• Investigation report
• Verification for effectiveness

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DEFINITION

• Correction An action to eliminate a detected
  nonconformity. Remedial action
  Repair, rework, or adjustment
• Corrective Action The action taken to eliminate
  the causes of an existing nonconformity, defect
  or other undesirable situation in order to
  prevent recurrence.
• Preventive Action The action taken to eliminate
  the cause of a potential nonconformity, defect,
  or other undesirable situation in order to
  prevent occurrence.
• Nonconformity non-fulfillment of a specified
  requirement. Any material or process that
  does not meet its required specifications or
  documented procedure.
• Note There is no definition for CAPA in the drug
  cGMP regulation

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ROOT CAUSE

• Root Cause identification is the most important
  step
• Root Cause Analysis (RCA) is a systematic
  approach to identify the actual root causes of a
  problem.
• CAPA will be effective to eliminate the
  reoccurrence if root cause is identified
  correctly and accurately

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21CFR Requirement( As per Medical device)

• 21 CFR 820.100(a) Regulatory Requirement -
  Establish and maintain procedures for
  implementing corrective and preventive action
• 21 CFR 820.100(a)(2) Investigate to Determine
  Root CauseInvestigate the cause of
  nonconformities relating to product, processes,
  and the quality system
• 21 CFR 820.100(a)(3) Identify Corrective and
  Preventive ActionsIdentify the action(s) needed
  to correct and prevent recurrence of
  nonconforming product and other quality problems
• 21 CFR 820.100(a)(4) Verify/Validate Corrective
  Preventive ActionsVerify or validate the
  corrective and preventive action to ensure that
  such action is effective and does not adversely
  affect the finisheddevice

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Preamble

• There are several investigation tools for
  deviation / OOS/ complaint investigations
• Use effective tool to identify the root cause
  usually with the use of a single tool.
• Complex investigations may require two or more
  different tools
• Familiar tools used widely are
• WHY -WHY analysis
• Fish Bone Analysis

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Investigation Tools

• RCA Technique/ Methodology
• Why- Why analysis
• Brain storming
• Cause and Effect / Ishikawa / Fishbone Diagram
• Fault Tree Analysis (FTA)
• FEMA etc

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Want to solve the problem !Think Differently
We can not Solve our problems with the same
thinking we used when we created them -Einstein

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How to Report Deviation OOS

• Description Describe clearly the
  Problem/Failure.
• Determine What, Why, Where, When, Who, How?
• Immediate Actions taken Contain/ stop continue
• Immediate ( known ) Product Quality Impact
• Complete the above within 24 hours from time of
  an incident identified
• Initial ( preliminary ) QA Review
• Above section must be completed within 2 days of
  receipt
• Complete the investigation as per SOP (preferably
  3-5 days)

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Investigation

• Objective Prevent the similar failure by
  effective CAPA.
• Seven steps of CAPA
• Identification Clearly define the problem
• Evaluation Appraise the magnitude and impact
• Investigation Make a plan to research the
  problem
• Analysis /RCA Perform a thorough assessment
• Action Plan CAPA -Create a list of required
  tasks
• Implementation Execute the action plan
• Follow Up Verify the effectiveness
• Do not release the deviation /OOS batch.
  until establish the conclusion

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Deviation/Incident Reporting

• State the incident Clearly /measurable terms
• What, When, where, how often, how much,
• Emphasize the quality risk,
• safety, death, injury, rework, etc.
• Do not write incident as
• negative descriptors, inflammatory statements
• words that are broad and do not describe the
  conditions or behaviour such as careless,
  complacency, neglect, oversight etc

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Deviation/Incident Reporting

• If An Incident /problem is well defined , a
  problem half solved
• Keep in mind it is to Correct, Prevent
  Improve
• No shortcut to conclude as human error
• 5W
• What is affected
• Where does the problem takes place
• When is the problem indentified
• Who is indentified
• What is the consequence
• 2H
• How much is affected
• How often has the problem occurred

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Investigation Process

• Review past history /similar issue
• Review records and documents
• Review process/operations
• Review the situation/ environment
• Interview people closest to the problem
• Inspect and test the product/ material
• Gemba-Inspect equipment facilities at site

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Investigation Steps

• Information must be captured from the people who
  were involved
• Gather the facts quickly to avoid the loos of
  information/ evidence
• Determine what historical data is available
• Determine what is known rather than what is from
  memory

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Investigation Report

• Record the details
• Location
• Date and time of occurrence, discovery
• Personnel ( titles / names ) involved
• Explain why the event is different from what is
  expected
• Initial scope
• Product / materials
• Lot/batch / campaign
• Equipment / train

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Review of Documents

• Review of BPR
• Review of Test data/records
• Review of situation surround of an incident
• Review of Systems / facility/ Equipment
• Eg. Environment, Log book, cleaning, handling
• Verify any such past incidence report
• Any additional testing required

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Root Cause Analysis (RCA)

• Root cause and the weed
• Weeds can be difficult to remove once they start
  to grow and spread.
• To eradicate the weed you have to get below the
  surface, identify the root, and pluck it out.
• Thus, you have to go beyond the obvious,
  ascertain an accurate route cause, so the
  appropriate corrective action can be pursued to
  prevent recurrence.

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Root Cause Analysis (RCA)

• A root cause is a system or a process that
  caused the problem you observed.
• Root Cause That condition, action, or lack of
  actionthat led to the problem occurring.
• Root Cause Analysis The process of identifying
  all the causes (root causes and contributing
  causes) that have or may have led to an
  deviation.

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Possible Reasons for Failure

• Human Error
• Equipment Failure
• Procedure is Inadequate or Not Clear
• Procedure not Followed
• Training Inadequate
• Design Error
• Poor Communication

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What are Human Errors?

• A mistake made by a person rather than a machine
  that produces a result that is Undesirable
• The organization does everything to prevent the
  problem.
• However, the employee ( operator/ peer/
  supervisor/ management ) still make a mistake
• Everyone can make error no matter how well
  trained and motivated

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Human Error or Violation?

• Two types of human failure Errors and
  violations.
• Identify them correctly and to be addressed
  appropriately
• A laboratory technician performing two tests
  simultaneously , but used the wrong sample for
  one of the tests
• A production operator filled out a cleaning
  record without performing the task
• A violation is a deliberate deviation from a rule
  or procedure.
• What influences to Error or Violation
• Eg Time pressure, design of controls,
  procedures, training and experience, fatigue, and
  levels of supervision etc.

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Human errors occur due to
A bad systemwill beat a goodperson every
time -W. Edwards Deming

• Inattention
• Memory lapse
• Failure to communicate
• Exhaustion /poor working conditions
• Ignorance
• A number of other personal and environmental
  factors
• Poorly designed equipment / facility.
• Eg Temperature gauge is fixed at roof or
  operation in ground floor , values fixed at first
  floor

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Human Error

• Human errors are not root causes
• Human errors are symptoms or consequences of
  deeper causes
• Develop error-tolerant systems to prevent errors
• Design of the job, equipment, procedures, and
  training.
• Change the People
• Without Changing the System and
• the Problems Continue.
• -Don Norman
  

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Human Error Type
Error Type Definition
Inadequate process Process does not achieve correct outcome
Incorrect procedure Procedure does not reflect the process
Lapsed/ no training Training/competency assessment out of date, not completed
Inadequate training Training/competency assessment does not cover error made
Ineffective training Training is adequate, but misunderstood
Procedural steps Procedural steps missed out (Intentional omitted or forgotten)
Concentration maybe due to rushing Steps in the process have been completed, but not accurately
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• You Cant Solve A Problem Until You Are Asking
• The Right Question

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5 Why analysis- Sakichi Toyoda

• A simplistic approach exhausting the question
  Why?
• It is like FTA and brain storming
• Preferred for investigations of specific
  deviations as opposed to chronic problems.
• Asks why events occurred or conditions existed
  iterative questioning
• Drills down to the root cause
• By repeatedly asking the question Why?, until
  symptoms and identify the Root Cause of the
  problem.
• Each Why bring Obvious Excuses
  Reasons Causes Root causes

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Disadvantages of 5 Why Analysis

• This time consuming brainstorming process may be
  tedious for team members trying to reach
  consensus.
• Results are not reproducible or consistent.
  Another team analyzing the same issue may reach a
  different solution.
• Some time Root causes may not be identified.

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Kepner Treqoe Matrix ( Questions)
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Cause and Effect /Fishbone Diagram

• It is also called as Ishikawa Diagram
• Establish a team which possess knowledge on this
• Write the Problem Statement at Head of a Fish
  bone.
• 6M or 5ME As Main Branch Manpower, Machines,
  Materials, Methods, Measures, Milieu /
  Environment.
• Identify the main categories of possible causes
• Add the sub-branch/factors in the diagram until
  to get useful information.
• Place these at ends of branches emanating from
  the back bone.

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Cause and Effect /Fishbone Diagram

• Brainstorm all possible causes and place these in
  the suitable area of the diagram.
• Use checklist /questions to support brainstorming
  
• Do not discourage the members ideas
• Analyze the results of the fishbone after
  obtained adequate detail to identify most likely
  causes.
• List most likely causes in priority order. First
  item being the cause or most probable cause.
• Typical Fishbone diagram....

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Typical Fishbone Diagram
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Example of Fish Bone Questions

• Measurement
• Is process performed as per established
  parameters?
• Are all measurement /entries / data correct?
• Calculations correct and verified?
• Are measuring devices appropriate, qualified
  calibrated?
• Do previous inspection or maintenance results
  indicate potential problems?
• Is quantity of input and output correct. Is
  quality suitable
• Is there any previous atypical results or
  trending history ie OOT
• Recent documentation history?

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Example of Fish Bone Questions

• Method / Process
• Is the process validated?
• Is the process operating within its validated
  parameters?
• Any deviations from standard operating
  procedures?
• Is the right procedure used?
• Is the procedure accurate / clear?
• Samples pulled at appropriate steps?
• Any sampling issues?
• Were processing steps properly verified?

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Example of Fish Bone Questions

• Machine/Equipment
• Has equipment been recently replaced or repaired?
  
• Is qualified and suitable assessed
• It is within calibration?
• Is preventative maintenance completed?
• Maintenance records reviewed?
• Are any equipment cleanliness issues?
• Equipment capacity or availability an issue?
• Is equipment being used for its intended purpose?
  

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Example of Fish Bone Questions

• Materials
• Are material / components tested approved ?
• Is properly released and issued ?
• Are materials charged correct quantity in
  sequence?
• Material properly stored temperature /
  humidity?
• Is within expiration dating?
• Is properly labeled segregated adequately?
• Is it from new source / vendor?
• Material sensitive/ protected

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Example of Fish Bone Questions

• Environment
• Is any environmental condition that contributed
  to failure?
• Is temperature maintained in the area and
  product ?
• Is equipment / room properly cleaned?
• Is cleaning validated?
• Cleaning agent /sanitization solutions used is
  appropriate ?
• Check the conditions Air Flow, Pressure,
  Temperature, RH
• Is any other activity performed at the same time
  that could contributed
• Is personnel monitored and maintained within
  limits

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Example of Fish Bone Questions

• People /Men
• Are personnel properly trained in the procedures?
  
• Are the operators familiar with the activity?
• Are adequate number of personnel worked in the
  particular procedure?
• Verify break/ shift change or any other issue
• Is adequate oversight of operators possible?
• Are procedures available to operators conducting
  the activity?

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Fault Tree Analysis

• FTA can be used to investigate complaints,
  deviations, unusual events
• It is a kind of deductive procedure used to
  determine failures and human errors that could
  cause Failure/ undesired events
• Approach to failure of the functionality of a
  product or a process.
• FTA is pictorial presentation of the fault modes
  based on logical reasoning
• FTA build by probable causes to identify
  potential causes of system failure before actual
  failure occur.
• Conclusion after completing an FTA.

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Fault Tree Analysis Steps

• Define the fault condition and write down the top
  level failure.
• Using technical information and professional
  judgments, determine the possible reasons for the
  failure to occur and write down below the failure
  in the tree..
• Continue to break down each element with
  additional gates to lower levels.
• Consider the relationships between the elements
  to help you decide whether to use an "and" or an
  "or" logic gate.
• Finalize and review the complete diagram. The
  chain can only be terminated in a basic fault
  human, hardware or software.
• If possible, evaluate the probability of
  occurrence at each elements

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Typical Fault Tree Analysis Diagram
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Fault Tree Analysis Diagram
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Rules followed for FTA

• FTA shall focus on the decision of experts from
  various disciplines and provides common outlook
  for the problem.
• Agreements and differences in opinion on the
  inputs and importance are considered in FTA.
• Members has to be encouraged, not likely to feel
  threatened.
• FTA shall focus on how the system operates, not
  personnel.
• Graphic shall Identify the possible causes of
  failure.

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Avoid during Investigation

• Do not focus Who made a mistake? Focus on
  Why did this go wrong?
• To avoid reaching erroneous / incomplete
  conclusions in the rush state.
• Scope and extent of failure is not understood
  fully
• Being superficial ( at symptom level ) and not
  reaching the depth ( at root cause level ).
• Lack of timely conclusion leading to improper
  product realisation.
• Thus failure is subsequently repeated.

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OOS Reporting Investigation

• Description clearly state the problem
• Phase1 Check list Chemist supervisor
• Hypothesis test
• Retest
• Investigation
• Laboratory / Manufacturing
• RCA investigation tool / methodology
• Fishbone diagram- men/ method/material/machine
• Process details/ analysis detail
• CFT QA, QC, Production Technical service,
  Engineering , RD etc
• Identify Other Batches Potentially Affected
• Justify Selection Consider distributed lots
  if any
• Conclusion
• Documentation

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Evaluation of product Impact

• Evaluate Product Impact / Disposition
• Additional testing / results
• Provide reason for accept / rejection of the
  batch
• Justify the exclusion of other batch if required
• Consider toxicological evaluation if required
• Reprocess/ reworking
• Stability

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Investigation Document Review

• Review all documents and records of the
  manufacturing process.
• A written record of the review includes
• A clear statement of the reason
• Summary of manufacturing process aspects that
  could cause the problem
• Results of documentation review with probable
  cause.
• Results of previous reviews
• Description of corrective actions to be taken.

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Resolution

• Typical Resolutions to Causes
• ? Procedural changes / updates
• ? Process Changes
• ? Engineering changes
• ? Process validation
• ? New training programs
• Typical Resolutions to Symptoms
• ? Fix it /Re-work / Correct
• ? Re-Training
• ? Disciplinary action

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Conclusion of Investigation

• If a cause is found, invalidate the initial
  result and use the retest value(s) in its place.
• If the OOS is confirmed the batch is rejected.
• If the OOS is inconclusive and the retests are
  within specification, then QA may be able to
  justify releasing the batch.

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Contents of Investigation Report

• Reason for the Investigation
• What event or finding initiated the
  investigation
• How and when Identified
• Evaluation
• Consider related activities and impact (immediate
  overall)
• Describe What Happened
• When
• Where
• What immediate actions were taken

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CAPA

• Identify Corrective Actions
• Resist operator error corrected with retraining
• May include additional monitoring / assessment
• Implementation must be timely
• Identify Preventive Actions
• Success depends on adequate identification of
  root cause
• Interim solution may include additional
  monitoring

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Effectiveness Verification of CAPA

• After implementation of CAPA effectiveness has
  to be verified
• Check that proper controls are established
• Verify the proposed training / communications
• Verify that CAPA show the improvement and there
  is no such problem reoccurs
• Verify that all the recommended changes are
  implemented and documented
• Verify that implemented CAPA, is not have any
  other adverse impact
• Document the effectiveness verification

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• QA
• Thank you