Failure Investigations

8/7/2019 Failure Investigations

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Barbara W. Unger 1

Failure Investigations,

Inspectors Expectations

Barbara W.Unger

Don Hill and Associates Inc.(317) 582-1504

[email protected]

Managing Process Deviations andFailure Investigations

March 18-19, 2003Copyright 2003, Barbara W. Unger


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Topics to be Covered

Global Governing Authority

Expected Content of Deviation Report

Where Companies Have Difficulty

Example Citations

Summary

References


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Governing Authority, US

21 CFR 211.192 andMultiple OtherProvisions within 211

A

ny unexplaineddiscrepancyshall bethoroughly investigatedThe investigationshall extend to other batches that can havebeen associated with the specific failure ordiscrepancy. Awritten recordof the

investigation shall be made and shall includethe conclusions andfollow-up.


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Governing Authority

ICHQ7A, GMPs for Active Pharmaceutical

Ingredients

Any deviation from established procedures should be

documented and explained. Critical deviations should

be investigated, and the investigation and its

conclusionsshould be documented.

All deviation, investigation and OOS reports should be

reviewed aspart of the batch record review before thebatch is released.


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Governing Authority, EU

EC Guide to GoodManufacturing

Practice, Chapter 5

Any deviations from instructions orprocedures should be avoidedas far as

possible. If a deviation occurs, it should be

approved in writingby a competent person


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U.S. Legal Opinion

United States v Barr Laboratories, Inc.1993 Described Requirements forInvestigations

Specifies Content of Failure Report;Requires Listing and Evaluation of Lots

PotentiallyAffected;

Elements ofThoroughness Vary Depending

on Nature and Impact of the Event;

Defines Promptly as 30 days from Event


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Linkage of Systems

EVENT

Investigation

Corrective Action

Preventive Action

Root Cause

Identify All Lots

Consider All Possibilities

Product Impact

Lot Disposition


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Definition of Deviation

Departure from Written Instructions,

Unexpected Event,

Departure from cGMP;Identify Exempted Incidents, Generally Documentation

Multiple Systems Can be Problematic

Create Confusion and Difficult to Track

Minimize Notes or CommentsMany Should be Deviations with Abbreviated

Investigations

Scope and Definition


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Content of Investigation Report

Reason for the Investigation

What Event or Finding Prompted Investigation

How and When Identified

Remember to Consider Tracking / Trending Evaluation Consider RelatedActivities, Think Global

Describe What Happened

What

When

Where

What Immediate Actions Were Taken


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Identify Other Batches Potentially Affected

Justify Selection

Remember Distributed Lots

Identify Root Cause, Where Possible

Why, Why, Why

Document Factors Considered

Ensure Data Support ConclusionsAvoid Conjecture

Often a Multi-Disciplinary Exercise


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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 CauseInterim Solution May Include Additional

Monitoring


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Evaluate Product Impact / Disposition

Additional Testing / Results

Justify Accept / Reject Criteria

Justify if Differences in Lot Disposition

Remember to Consider Tox Evaluation

Provide Follow-up to Assure Effectiveness

Does Preventive Action Provide a Durable Fix

What are Criteria for Durable Fix


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Where are the Deficiencies?

Lack of Documented Investigation

Incomplete Investigation

Factors Not Considered / Documented

Associated Lots Not Identified / EvaluatedRoot Cause Not Established orJustified

Conclusions Not Supported by Data

Timelines Not Followed, Not Extended

Corrective / Preventive Actions NotImplemented, Tracked or Completed

Effectiveness Not Verified


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Operator Error is Not Specific

Operator Action

Inattention to Detail

Verbal or Written Communication Problem

Operator Monitoring Multiple Processes Operator Training:

Not Trained on Procedure

Not Trained on Current Version of Procedure

Insufficient Practice or Experience

Inadequate Content in Training


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Operator Error

Management System

Inadequate Administrative Control

Work Organization / Planning DeficiencyInadequate Supervision

Improper Resource Allocation

Information NotAdequately Defined,

Disseminated or Enforced


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Equipment

Equipment Failure Calibration Not Current

Multiple Work Order(s) Addressing Same Issue DidntCorrect Problem

Preventive Maintenance Not Current Out of Tolerance

Equipment Not OperatedAccording to ValidatedProcedure

Defective Part

Improper Part

No IQ/OQ or Inadequate IQ/OQ

Electrical Power Failure or Surge


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Example Citation, 2002

Unknown Peak, 13 Lots ofTablets

Initial Investigation Suggests Contamination in

Handling

18 Months Later, Investigation Indicates Toluene

Toluene Source Not Confirmed Until Inspectors

Prompt the Company, Another 18 Months Later

Evaluation Revealed Ink as the SourceResponse to 483 Indicates Different Source for

the Toluene with No Supporting Data


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ThreeMonth Accelerated StabilityFailure

Investigation Did Not Indicate if Batch Records

Were ReviewedDid NotAssess All Possible Reasons for Test

Failure

Did Not Review Additional Batches

Did Not Indicate Corrective or PreventiveActions.


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Mechanic Discovered Black Particles in aNozzle During Primary Packaging

Particles Not Retained forAnalysis

Investigation Not Extended to Other Lots that UsedSame Equipment

Particles Concluded to be from Deteriorating

Butterfly Gasket but No Reason for Deterioration

No Evaluation of Product Impact Because Partial

Lot Released When Visual Exam Alone Could Not

Assure Absence of Particles


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Summary of Inspector Expectations

Implement and Follow an Adequate Procedure

Perform and Document ThoroughInvestigations and Testing Commensurate withEvent and Potential Impact

Adhere to Time Limits

Identify OtherPossibly Affected Lots

Evaluate Impact on Product

Implement and Evaluate Corrective /Preventive Actions

Quality Unit to Review and Approve Reportand Disposition Product


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Selected References

21 CFR 211 21 CFR 820, see Quality Systems

The Rules Governing Medicinal Products in theEuropean Community. Vol IV

ICH Q7A; cGMP for APIs

Opportunity for a Hearing, Barr Laboratories inFederal Register Vol. 58 No. 102, May 28, 1992,

pages 31035 31043

BioPharm, August 2001, pages 12-17, 63

BioQuality, all issues

BioPharm, October 2002, pages 36-40


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Selected References

Proposed US FDA Rule, cGMP: Amendment ofCertain Requirements for FinishedPharmaceuticals (Federal Register 61(87) 3 May

1996, page 20104) US FDA Guide to Inspection of Quality Systems

Investigating OOS Test Results forPharmaceutical Production (FDA, draft 9/1998)

US Department of Energy Guideline, Root CauseAnalysis Guidance Document, February 1992

US FDA Compliance Program Guidance Manual,7356.002

Failure Investigations

Documents

Transcript of Failure Investigations