DEVIATION INVESTIGATIONS A Proper Objective Perspective

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A Proper Objective Perspective

    FDA USP Conference
        Irvine, CA

      December 5, 2008

 Deviations (All departments)
 Out-of-Specification (QC Lab)
 Out-of-Trend (QC Lab)
    –   Raw Materials
    –   Components
    –   Containers/Closures
    –   API
    –   Finished Drug Product
   Associated with limits vs. specifications

   GMP mistakes or errors
    – Reprocessing or Rework
    – Unapproved changes
    – Performing an activity without proper training
    – Outside of operating parameters or in-process
      control limits
    – Failure to follow written SOPs or approved
      batch record instructions
   GMP mistakes or errors
    – Good documentation errors – missing entries,
      unexplained entries, improper corrections or edits
      to official records
    – Environmental Monitoring over alert or action
      limit excursions
    – Out of calibration
    – Unplanned preventive maintenance or repairs to
      „qualified‟ equipment or systems
      Deviation Investigations
   Root Cause(s) – Thorough Investigations
    – What vs. Why or How
        The 20 : 80 (what : why/how) Rule

   Corrective Actions
    – Batch release dependent
   Preventive Actions
    – Batch release independent
       Deviation Investigations
   Deviation investigations must not be biased from
    the start
    – From an FDA or cGMP perspective, the purpose of
      conducting a deviation investigation is not to “release the

    – The true purpose of a deviation investigation is to
          determine the root cause for the “deviation”\
          implement appropriate and meaningful corrective actions, and
          evaluate the implicated system (e.g., the training program) once
           a pattern of repeating deviations is noted.
          Deviations Investigations
             vs. Batch Release
       (Product Impact Assessments)

Batch release should be considered a separate and distinct QA
function and activity!

Product Impact Assessments should be done “collectively”
(summation of all deviations) after an appropriate deviation
investigation has been completed.

All deviations must then be collectively evaluated at the time
of final batch release.
               Root Cause(s)
   Documenting all attempts to identify, determine,
    confirm, or rule out potential root cause(s)
    – Why and how did it occur
 Detailed descriptions (what, where, when, and
  who) of the deviation vs. root cause investigation
  or assessments
 Definitive or Potential Root Cause(s)
           Root Causes

   Definitive vs. Potential Root Causes

          Corrective Actions
 Short term, immediate actions taken to “correct”
  or address the potential root cause(s) for each
  reported deviation
 Actions designed to eliminate or minimize the
  potential for recurrence of the deviation
 Must be initiated (accountability in a formal
  quality system) or completed prior to closing out
  of the investigation
 Corrective actions should be tracked and trended
  in a quality system
        Corrective Actions

    General FDA 483 Observation

Corrective actions do not „match‟ or support
     definitive or potential root causes.
          Preventive Actions
 Longer term actions designed to determine the
  effectiveness of corrective actions
 Actions designed to ensure the “prevention” or
  recurrence of deviations
 Preventive actions do not have to be initiated or
  completed prior to closing the investigation
 Preventive actions should be tracked, monitored
  for completion, and trended in a quality system
      Preventive Actions

Preventive actions must focus on „system‟
evaluations and „system‟ level continuous

Quality system improvement is more important
to FDA than corrective actions (band-aid fixes
necessary to just release a batch).
    FDA’s Chronologic Expectations
   Deviation reported in real time
    – Timely notification of QA (within 24 hours)
   Thorough root cause investigation
   Timely investigation (within 30 days)
   Corrective actions proposed and initiated or completed
   Investigation closed
   Implicated batch(es) released or rejected
   Preventive actions initiated and closed
          Planned Deviations
 Planned deviations should be handled through the
  QA approved change control procedures.
 All changes should be evaluated for product
  impact, significance
    – The need for requalification or revalidation
    – Changes ultimately approved or rejected by QA.
 QA should insist that planned deviations not be
  used; all deviations should be unintentional,
  unplanned, or unexpected.
 Shutdown or validation protocols can also be used
  in lieu of planned deviations.
Deviation vs. Out of Specification
   Preliminary investigation
    – Purpose: Investigate to determine if the initial OOS test
      result is valid or invalid based on a review of the bench;
      do not discard sample preparation, pipettes, etc.
          Analyst error
             – Sample preparation error
          Instrument error
          Reference standard
          Calculation error
          Failure to follow test method
Deviation vs. Out of Specification

 Once confirmed, invalid OOS test results
  should be converted to deviation
 Confirmed valid OOS test results should be
  investigated through the OOS procedure
    – Link to the failure investigation procedure for
      rejected materials, API, and/or finished product
        Deviation Management
        Business Perspective
   Measures of efficiency and productivity
    – Qualified suppliers
    – Higher yields
    – Process Optimization
   Routine global senior management visibility
    – Competitive business strategic plans
   QA quality systems evaluation
    – Regulatory insurance policy (CGMPs)
   Mission or Vision Statements
    – “Do it right the first time”
    – “Quality First”
                 Final Thoughts
 Deviation investigations are not an unusual or
  foreign concept to industry or in our normal
  outside of work life
 Workers compensation or injury at work
    – Consider steps taken with respect to EHS (safety or
      injury related) investigations, corrective action, and
      preventive action program.
    – Corrective actions are designed to target root cause(s).
    – Preventive actions are designed to ensure corrective
      actions are effective in avoiding work related injuries
      through appropriate „system‟ level improvements.
Contact Information
CDR Jeffrey T. Yuen, MPH, MBA
 President – Principal Consultant

    Jeff Yuen and Associates
          P.O. Box 6026
    Orange, CA 92863-6026

        Phone: 714 282-1014
        E-Fax: 240 597-8351

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