Effective Investigations and Corrective Actions(CAPA)ipapharma.org/events/reports/Anisfield -...

© Copyright, Globepharm Consulting, 2008 1

Effective Investigations and

Corrective Actions (CAPA)

P I i i f Q li EProper Investigation of Quality Events

Michael H. AnisfeldGlobepharm Consulting

What Do You Do When The Bad Stuff Happens?

I It Pretend It Never HappenedIgnore It

Advise Boss Curse

Walk AwayIt’s a One-Off

Advise Your Buddy

Pretend It Never Happened

!#&*!$%...

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Fix It

Blame Someone Else

Investigate + Fix

Investigate, Fix + Document

Investigate


Failure/Deviation System

Th f f il /d i i i The purpose of a failure/deviation system is to assure that each failure/deviation does not adversely impact product quality and that effective corrective action is taken to reduce the probability of such failure in the future

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Contributors to Failure

MaterialsFacilitiesEquipmentInstrumentationPeople

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PeopleProcessesProcedures

Failure / DeviationDefinition

F ilFailureProduct does not meet specification.Failure may be detected in/by

ProductionLaboratory

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DeviationChange in procedures, equipment, materials, personnel related to product manufacture having an impact on product quality


Definitions

Immediate CauseSituation directly causing the problem

Root CauseBasic Causal Factor, which if corrected or removed prevents a repeat of the problem

Intermediate CauseReason for problem at more fundamental level than the

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Reason for problem at more fundamental level than the immediate cause, but not the root cause [why-2, why-3]

Root Cause AnalysisStructured questioning process enabling identification of underlying beliefs and practices that result in poor quality

Causes of Failure

C mm n C [End mi S t m ti ] (V i ti n)Common Cause [Endemic – Systematic] (Variation)Originates from the basic elements of the process:

MachinesMaterialsMethodsManpowerMeasurement

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Assignable Cause [Special] (Variation)An unplanned variation originating outside expected

operating process conditions [special cause variation]


Failure/DeviationsMeasures

There are three key steps in this process and each of these should There are three key steps in this process and each of these should be monitored regularly

Recording the failures and deviationsTotal numberNumber by department

Action on product batch(es) involved

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Audit by sampling to verify that corrective action was taken

Corrective action on root causesThere should be an elimination of failures/deviations due to causes for which corrective actions have been implemented

Regulators Expectations

C h i H A h T Comprehensive, Honest Approach To Investigate OOS Results/Failures

Evaluation Using Scientifically Valid Principles

Learning From Experiences

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Permanent Solutions To Problem

Authorities Not The Ones To Find The Problem


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What to Do When the Unexpected Happens

UNEXPECTED?UNEXPECTED?OOS

LaboratoryManufacturing

Water SystemOOTOOEOOY

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Reconciliation – Yield CheckReconciliation – Packaging Material

DeviationDiscrepancyUnusual Event


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What Do The US Regulations Say?

“In ti ti n” p ifi ll t t d in th GMP :Investigation specifically stated in the cGMPs:

§211.22 - Responsibilities of quality control unit. §211.125 - Labeling issuance. §211.170 - Reserve samples. §211.180 - General requirements. §211.186 - Master production and control records.

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p§211.188 - Batch production and control records. §211.192 - Production record review. §211.198 - Complaint files. §211.204 - Returned drug products.


What Does The EU Guide Say?

“I ti ti ” ifi ll t t d i th GMP“Investigation” specifically stated in the GMPs:

1.3 Quality Assurance1.4 Quality Control2.7 Production/QC Responsibilities5 39 Production

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5.39 Production5.56 Packaging Operations6.2 Quality Control8.1 Complaints

Future Regulations

i i l h i d An international harmonized approach to

Risk Management

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ICH-Q9


initiate risk management process

risk identification

srisk assessment

ICH-Q9Risk Management

risk analysis

risk evaluation

risk reduction

i k tnage

men

t to

ols

risk control unacceptable

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risk acceptance

risk communication

Ris

k m

an

review event

risk communicationrisk acceptance

output/results of the risk management process

OK


CAPA

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How do you know what’s happening?

R i h h i blRecognize that there is a problem:Capture The DataAnalyze The DataTrend The Data

Then Fix the problem:

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hen Fix the problemInvestigate the CauseAttempt to Get to “Root Cause”Implement Effective FixesMonitor the Fix


21CFR820.100 - CAPA

§820.100 Corrective and preventive action(a) Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. The procedures shall include requirements for:

(1) Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems.

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g p , q y pAppropriate statistical methodology shall be employed where necessary to detect recurring quality problems;

(2) Investigating the cause of nonconformities relating to product, processes, and the quality system;

(3) Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems;

21CFR820.100 - CAPA

§820.100 Corrective and preventive action (continued)(4) Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device;(5) Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems;(6) Ensuring that information related to quality problems or

f mi d t i di mi t d t th di tl

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nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems; and(7) Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.

(b) All activities required under this section, and their results, shall be documented


CAPA – Analyzing Sources of Quality Data

E i l

CAPA

Complaints/Returns

Repairs/Ser icing

ProcessDeviationsor Failures

Acceptance Activities

Environmental Monitoring

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CAPAServicing

Calibration/Maintenance

StabilityData

Audits Yields/Scrap

What To Track

T k BTrack By:

Product In-process, release, stability, validation

Event Reason for investigation

Operator/Analyst If cause is operator/analyst error

Instrument/Equipment If cause instrument related

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Cause Investigation conclusion

Corrective Action Remedy and prevention

Timeliness Time to complete investigations


Incidents Reported - 2003

CAPA Data Collection

186 178

210

165 171

143132 130

119150

200

250

Incidents

Question:Are we Getting Better as a Company?Or Dropping Off in Capturing Incidents?

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9885 92

0

50

100

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Run Charts: Trend ChartsEnvironmental Data – Purified Water System

SpecificationSpecificationUpper Limit

OOT? / OOE?

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SpecificationLower Limit


Tracking / Trending

Paper/PenPaper/Pen

Spreadsheet (Excel, Oracle)

Dedicated Computer SystemsTrackwise

(Sparta Systems: http://www.sparta-systems.com) CATSweb

(AssurX: http://www.assurx.com/catsweb.html)

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pMetricStream

(Metric Stream: http://www.metricstream.com) SmartCAPA

(SmartCAPA: http://www.pilgrimsoftware.com)

Others …..

SmartCAPA®(www.pilgrimsoftware.com)

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Purpose of Investigation

Th f i i i i The purpose of an investigation it to determine the cause of the failure.

Even if the batch is rejected based on the OOS result, the investigation is necessary to determine if the result is associated with other batches of

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if the result is associated with other batches of the same drug product or other products

FDA: Draft OOS Guideline, September 1998


Failure / Deviation – What To Do

F il /D i ti D t t d I f QAFailure/Deviation Detected

Perform Investigation

Root Cause Analysis

Inform QA

Batch Disposition

Immediate Fix

24 hours

30 days

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Communicate to Management

Corrective/Preventive Action

Assess Effectiveness of Fix

Investigations: You’ve Got to Be A Detective!

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Investigations 101

P p f n In ti ti nPurpose of an InvestigationObtain facts as to cause

CommonSpecial - Assignable

Process of an InvestigationComplete description of problem

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p p pValidity of inputsReview key process variablesDetermine scope of investigationDocument investigation

Learn How To Be A Detective

What Equipment What Equipment, Machine, Tool?

What Is Wrong?

What Is the

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What Is the Complaint?

What is the Undesired Behavior?



Wh i I l d?Who is Involved?StaffConsultantsVendorsVisitors

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Name names/positions!


Wh d th bl When does the problem occur?

DayDateTimeShiftPhase of operation

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Phase of operationWhen in equipment life cycle

Are there time patterns?



Whi hWhich:UnitAreaDepartmentLineMachine

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Location of defective item, or where on defective item


How is the “what” or “who” How is the what or who impacted?

Injury / DeathShut-Down /Start-UpDamageType Classification of Defects

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How MuchHow ManyHow Big An Issue

What resources are needed to handle/resolve the issue!


Change Analysis

EPROBLEM? COMPARISON?

WHAT?What is the object or

process with the problem?What is wrong?

What similar object or process doesn’t have the

problem? What else could be wrong?

WHERE? Where does the problem occur

Where else could the problem occur?

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occur problem occur?

WHEN? When did the problem happen?

When did the problem not happen?

HOW BIG? How large is the problem? How large could it be?

Investigation Documentation

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A B C D E


Investigation Documentation

D t p bl m dDate problem occurredStatement of the Problem Listing of batches impactedList of personnel interviewedStatement of each person’s opinions and memory of eventDiscussion of potential causesDiscussion of potential impact

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Discussion of potential impactDiscussion of extent of problemRecommendations for fixesStatement of actions taken to fixFinal decisions regarding batchManagement approvals

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Root Cause Analysis

C ti ti t b ti ( ll t ) Corrective actions to observations (usually symptoms) have limited effect on sustained improvement or elimination of recurrence of the failure

Corrective actions need to address the underlying causes and root causes of a problem in order to

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eliminate the situation from recurring

Root Cause Analysis

EquipmentDesign Capability

Management SystemsQualified SupervisionDesign, Capability

MaintenanceOperator Error

ProceduresNo ProcedureWrong Procedure UsedProcedure Not AvailableProcedure Difficult To Use

TrainingNone

Qualified SupervisionAuditsFeedbackPrior Corrective Actions TakenCommunicationPlanningProcess CapabilityAdequate Time To Perform TaskStandards

ManpowerInformation Available

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NoneWhenEffectiveness

Quality ControlInspection RequiredInspection Performed

Information AvailableAdequateTimely

Personnel ProblemsTrainingFail/Safe ProcessesEnvironment

LightingNoise

Fatigue


Corrective Action

Wh i h l l l hi h What is the lowest level at which we can do something to prevent the problem from re-occurring?

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Investigation Tools

B i t th iBrainstorm the issuesFlowchartingFishbone Analysis – Cause/Effect diagramsWhy-Why AnalysisPareto ChartsRun Charts

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Run ChartsForce Field AnalysisSix-Sigma Analysis - MAICKepner-Tregoe®

Brainstorming

P ibl t t ti t th f l i t f Possible target questions to serve as the focal point of the brainstorming process:What would solve the problem?What strategy could resolve the root cause?What solutions have already been thought of?What solutions have not been thought of?

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What solutions have not been thought of?How can we prevent the situation recurring?What different methods might work?What crazy ideas might help?


Fishbone Analysis

Manpower Management

Batch

People too busyPeople not paying attention

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Methods Machines

RecordErrors

Why-Why Analysis

Oil D O FlOil Drops On FloorDripping EngineOil Can to CollectFunnel in Oil CanRaise Funnel

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Raise FunnelUnless you’ve gone 5 levels of questionsyou probably have not got to root cause!


Pareto Analysis

Pareto: 80 – 20 rule

87

50

60

70

80

90

Batch Record Problems

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2318

12

0

10

20

30

40

Signatures Data Errors Other

Process Shift, F-440 Particle Size


APR – Annual Product Review

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Force-Field Analysis

Th P iti /N ti Wh t ld k Wh t ld k The Positive/Negative Analysis for Solutionscan stimulate thinking just as a the force-field format did in the past. Since we are looking for solutions, the two columns play “better”

What would make the problem

better?

What would make the problem

worse?1.2.3.4.

1.2.3.4.

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columns play better against “worse”.

4.5.6.7.8.

4.5.6.7.8.


Six Sigma Problem Solving – MAICMeasure Analyze Improve Control

(12) ImplementSolution

(9) Determine Best Solution(4) Identify PotentialCauses

(1) Describe theProblem

(5) Analyze Existing Data

0 251

(10) Pilot Solution

(2) Determine WhenProblem Started

(6) Construct List ofVerified Facts

LSL USL

Item Function Failure Mode Causes Effects Control

Control Plan(2) Lid Prevents Spills Lid falls off due

to looseness

Leaks from drinking hole

Spill when removing lid

Lid diameter too large

Body diameterto small

Surfaces too slick

Hole too large

Hole has toodirect of path

Lid diameter too small

Body diameterto large

Material catches

Burn

Burn

Burn

Stain

Stain

Burn

Burn

Burn

Go-no go gauge

Go-no go gauge

Sampling Plan

Pin gauge

(above)

(above)

Sampling Plan

(7) Compare Causes to Facts

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12.5

IS NOTIS

WhatWhereWhenExtent

(11) Verify Solution Works

1 2 3 4

T M B T M B T M B T M B

0.251

0.250

0.249

0.248

Fact

1Fa

ct 2

Fact

3Fa

ct 4

Fact

5

Cause 1 O X X O ACause 2 X O A A OC 3 O O A A O

FACTS(1) All Machines(2) Second Shift(3) Certain Codes(4) Started 8/22

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(8) Collect Additional Data Until Root Cause Identified(3) Measure Problem

Magnitude

15 20 25 30 35

Seal Strength

2 4 6 8 10

Percent Defective

0.0

0.5Pa

1.0

0

OC Curve

© Copyright 2000, Taylor Enterprises Inc.

70

60

40

30

50

TORQUE

L36.0 37.0 38.0

K = 20

K = -20

6

Jan '87 Jul '87 Jan '88 Jul '88

Month

Subgroup

1 5 10 15 20

10.2

10.0

9.8

9.6

Radius

Upper Control Limit

Lower Control Limit

Cause 3 O O A A OCause 4 X A X O OCause 5 O O O O X

(4) Started 8/22(5) Steadily Worse(6) All Operators

A B C E HCode

Num

ber

D F G

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initiate risk management process

risk identification

srisk assessment

ICH-Q9Risk Management

risk analysis

risk evaluation

risk reduction

i k tnage

men

t to

ols

risk control unacceptable

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risk acceptance

risk communication

Ris

k m

an

review event

risk communicationrisk acceptance

output/results of the risk management process

OK

Tools To Prioritize Fixes and Efforts

FME F il M d Eff l iFMEA - Failure Mode Effect Analysis

FTA - Fault Tree Analysis

HACCP Hazard Analysis

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HACCP - Hazard Analysis, Critical Control Points


BibliographyRoot Cause Analysis:

- Kepner and Tregoe, “The New Rational Manager”- Paradies and Unger, “Taproot: The System for Root Cause Analysis,

Problem Investigation & Proactive Improvement”- Ammerman “The Root Cause Analysis Handbook”- Ammerman, The Root Cause Analysis Handbook- Pokras, “Systematic Problem-Solving and Decision-Making”

Risk:McDermott et al., “The Basics of FMEA”

Human Error:Lorenzo, ABS Consulting, “A Manager’s Guide to Reducing Human Error”

Management’s Role:

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gHarbour and Kieffer, “Managing the Quality System”

FDA:“Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production” (Guidance), September 1998Quality Systems Approach to Pharmaceutical GMPs, September 2004

Mi h l H Ani f ld

Stay In Touch

Michael H. AnisfeldGlobepharm Consulting313 Pine StreetDeerfield IL 60015, USA

Phone: USA +1+847 914 0922

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Fax: USA +1+847 914 0988E-mail: [email protected]: www.globepharm.org


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Questions?

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