DEVIATION INVESTIGATIONS A Proper Objective Perspective

1. DEVIATION INVESTIGATIONS A Proper Objective Perspective FDA USP Conference Irvine, CA December 5, 2008

2. Investigations • Deviations (All departments) • Out-of-Specification (QC Lab) • Out-of-Trend (QC Lab) • Raw Materials • Components • Containers/Closures • API • Finished Drug Product

3. Deviations • 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

4. Deviations • 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

5. 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

6. 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 batch.” • 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.

7. 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.

8. DeviationsRoot 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)

9. Root Causes Definitive vs. Potential Root Causes THERE IS A BIG DIFFERENCE BETWEEN WHAT HAPPENED VS. WHY OR HOW SOMETHING HAPPENED!

10. 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

11. Corrective Actions General FDA 483 Observation Corrective actions do not ‘match’ or support definitive or potential root causes.

12. DeviationsPreventive 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

13. Preventive Actions Preventive actions must focus on ‘system’ evaluations and ‘system’ level continuous improvement. Quality system improvement is more important to FDA than corrective actions (band-aid fixes necessary to just release a batch).

14. DeviationsFDA’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

15. 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.

16. 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

17. Deviation vs. Out of Specification • Once confirmed, invalid OOS test results should be converted to deviation investigations • 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

18. Deviation ManagementBusiness 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”

19. 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.

20. 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 E-mail: jtyassociates@prodigy.net

21. Reproduction or Copies Further reproduction, copies, or use of this presentation without explicit permission from Jeff Yuen and Associates is strictly prohibited. November 13, 2003