DEVIATION INVESTIGATIONS

A Proper Objective Perspective FDA USP Conference Irvine, CA December 5, 2008

Investigations

Deviations (All departments) Out-of-Specification (QC Lab) Out-of-Trend (QC Lab)

Raw Materials Components Containers/Closures API Finished Drug Product

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

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

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 batch.

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.

The true purpose of a deviation investigation is to

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.

Deviations 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

THERE IS A BIG DIFFERENCE BETWEEN WHAT HAPPENED VS. WHY OR HOW SOMETHING HAPPENED!

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.

Deviations 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 improvement. Quality system improvement is more important to FDA than corrective actions (band-aid fixes necessary to just release a batch).

Deviations
FDAs 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 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

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
E-mail: jtyassociates@prodigy.net

Reproduction or Copies

Further reproduction, copies, or use of this presentation without explicit permission from Jeff Yuen and Associates is strictly prohibited.