Effective Control of theEffective Control of the Examination ProcessExamination Process

Group 2 ReportGroup 2 Report““Reunion de Reunion de ExpertosExpertos””

5 CICLO International De 5 CICLO International De ConferenciasConferencias De La De La CalidadCalidad

11

Group 2 Participants

Laura Mercapide, Argentina

Amadeo Saez, Brasil

Aida Porras, Colombia

Oscar Martinez, Colombia

Arturo Terres, Mexico

Eduardo Brambila, Mexico

Enrique Amaya, Peru

Margarita Iturriza, Venezuela

Erik Mendoza, Mexico

James Westgard, United States

Our Focus is on the Examination Process

Pre-analytic and post-analytic errors are also of concern, but our charge is to focus on the analytical part of the examination process

Evidence in scientific literature indicates analytical errors are still major source of problems leading to mistreatment and harm to patients

What errors have been observed in What errors have been observed in the Total Testing Process?the Total Testing Process?

Pre-analytic Analytic Post-analytic

•Patient preparation•Specimen acquisition•Specimen processing•Sample transport•Physician test order

•Sample aliquot•Analyzer setup•Test calibration•Quality control•Reportable test

•Test report•Transmittal of report•Receipt of report•Review of test results•Action on test results

60% 15% 25%Plebani & Carraro. Clin Chem 2007:53:1338-42

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Lab Errors and Patient CareLab Errors and Patient Care

PlebaniPlebani--CarraroCarraro study study

ClinClin ChemChem 2007:53:13382007:53:1338--4242

51,746 tests 51,746 tests

393 questionable results393 questionable results

160 confirmed as laboratory errors160 confirmed as laboratory errors

46 caused inappropriate patient care46 caused inappropriate patient care

24 of those were analytical errors24 of those were analytical errors

Analytical errors are still major cause (over Analytical errors are still major cause (over 50% cases) of inappropriate patient care50% cases) of inappropriate patient care

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Need for Guidance on “Effective Control of Examination Process” for

Latin American Countries

Important to be relevant and practical for local laboratories

Must consider national and governmental interests and requirements

Must consider professional assessment of needs and practice guidelines

General guidance on General guidance on ““effective effective control of examination processcontrol of examination process””??

ISO 15189: Medical Laboratories ISO 15189: Medical Laboratories –– Particular Particular requirements for quality and competencerequirements for quality and competence

ISO 15198: Validation of user quality control ISO 15198: Validation of user quality control procedures by the manufacturerprocedures by the manufacturer

CLSI C24CLSI C24--A3: Statistical Quality Control for A3: Statistical Quality Control for Quantitative Measuring Processes Quantitative Measuring Processes –– Principles Principles and Definitionsand Definitions

CLSI EP23CLSI EP23--P: Laboratory Quality Control based P: Laboratory Quality Control based on Risk Managementon Risk Management

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ISO 15189 Guidance for ISO 15189 Guidance for ““Assuring Assuring QualityQuality”” of Examination Processof Examination Process

5.6.1. 5.6.1. ““The laboratory shall design The laboratory shall design internal quality control systems that verify internal quality control systems that verify the attainment of the the attainment of the intended quality intended quality of resultsof results…”…”

Medical relevanceMedical relevance of laboratory tests is an of laboratory tests is an important consideration!important consideration!

Comparability of test results is important for Comparability of test results is important for medical relevance!medical relevance!

How define medical relevance?How define medical relevance?99

ISO 15189 “Assuring quality”

5.6.2 ..determine uncertainty of results, where relevant and possible

5.6.3 …ensure that results are traceable

5.6.4 …participate in interlaboratory comparisons

5.6.5 …if EQA not available, develop a mechanism for determining acceptability

5.6.6 For examinations performed using different procedures or at different sites, define a mechanism for verifying comparability of results

Particular issues assigned to this work group

What frequency of QC is sufficient?

How important are recommendations from manufacturers for QC? Should laboratory modify recommendations?

How often for EQC or PT?

How assure quality?

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(3) Validate MethodPerformance (CV,bias)

(1) Define Goals for Intended Use

(TEa, Dint)

(3a) Manufacturer’sClaims

(1a) Regulatory &AccreditationRequirements

(1b) Clinical and Medical Applications

(2) Select AnalyticMeasurement

Procedure

(2a) Traceability& Calibration

(2b) Manufacturer’sReference Methods

& Materials

(4) Design SQC(rules, N, F)

(5) FormulateAQC Strategy

(11) Improve AQCEffectiveness

(5b) Lab Evaluationof Residual Risk

(5a) Manufacturer’sRisk Analysis

(6) Develop AQC Plan

(10) Monitor AQCEffectiveness (f), EQA

(7) Implement AQC System

(6a) QC Toolbox

(8) Verify Attainmentof Intended Quality

of Test Results

(9) Measure Quality& Uncertainty

What frequency of QC?What frequency of QC?

CLSI guidance on defining run lengthCLSI guidance on defining run length

““An analytical run is an interval (i.e., a period An analytical run is an interval (i.e., a period of time or series of measurements) within of time or series of measurements) within which the accuracy and precision of the which the accuracy and precision of the measuring system is expected to be stable; measuring system is expected to be stable; between which between which eventsevents may occur causing the may occur causing the measurement process to be more susceptible measurement process to be more susceptible (i.e., greater risk) to errors that are important (i.e., greater risk) to errors that are important to detect.to detect.””

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Factors Affecting Run Length (1)Factors Affecting Run Length (1) Events and nonEvents and non--eventsevents

Event driven QCEvent driven QC

Known, scheduled and expected changesKnown, scheduled and expected changes

NonNon--event driven QCevent driven QC

Other things that happenOther things that happen

ParvinParvin’’ss conceptsconcepts

Ref: Ref: ParvinParvin, , GronowskiGronowski. Effect of analytical . Effect of analytical run length on QC performance and the QC run length on QC performance and the QC planning process. planning process. ClinClin ChemChem 1997;11:21491997;11:2149-- 2154.2154.

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Factors Affecting Run Length (2)Factors Affecting Run Length (2) Mode of OperationMode of Operation

Batch modeBatch mode

All patient specimens and control samples are All patient specimens and control samples are analyzed togetheranalyzed together

Patient results not reported until control Patient results not reported until control results are validatedresults are validated

Continuous modeContinuous mode

Patient results are being reported as they are Patient results are being reported as they are determineddetermined

Control samples are analyzed periodicallyControl samples are analyzed periodically

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Factors affecting Run Length (3) Cost-Effectiveness

Number of controls relative to number of patient specimens

Costs of repeat analyses for out-of-control runs

Cost for number of levels of controls

Factors Affecting Run Length (4)Factors Affecting Run Length (4) StrategiesStrategies

ManufacturerManufacturer’’s instructions may provide s instructions may provide minimum strategy minimum strategy –– e.g., 2 levels per daye.g., 2 levels per day

+ Event QC to assess significance of + Event QC to assess significance of changes in the testing processchanges in the testing process

+ non+ non--event QC to monitor process during event QC to monitor process during routine operationroutine operation

MultiMulti--stage QC for stage QC for ““startup,startup,”” ““monitoring,monitoring,”” and and ““patient data QCpatient data QC””

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Factors Affecting Run Length (5)Factors Affecting Run Length (5) StrategiesStrategies

Sigma QC Sigma QC –– relative amount of QC can be relative amount of QC can be related to methodrelated to method’’s sigmas sigma--performanceperformance

Risk analysis and residual risks Risk analysis and residual risks –– guidance for guidance for susceptibility testingsusceptibility testing

Consensus of experts Consensus of experts –– professional practice professional practice standardsstandards

Experienced judgment Experienced judgment –– knowledgeable analyst knowledgeable analyst has expertise about stability and susceptibility of has expertise about stability and susceptibility of testing processtesting process

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Run length and frequency of controls

Models

Measures Statistical

Assumptions

Empirical

Economic

Residual risks

Error frequency, f Q/P

Strategies

Sigma

Risk analysis

Consensus of experts

Event+Monitor

Manuf. recommendations

Batch processing

Experienced judgment

Residual risksEvent only

Cost of repeat analysis

Operations

Batch mode

System stability

Continuous mode

Reporting interval

Unexpectedevents

LIS

Susceptibility

Batch size

Components

Residual risks

Maintenance

Calibration, reagents

Analyte stability

Events

Operators

PartsLab conditions

Stats

QC performance goals

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What frequency of QC is sufficient? Recommendations (1)

Strategy

Define length of run

In terms of time, numbers of patient samples, mode of operation

Importance of “events” or changes that occur with the process that require verification by controls

Medically important concentrations for controls

General practice to use two levels of controls

Sometimes advisable to have three levels

Many factors to consider to optimize run length or frequency of QC

What frequency of QC? Recommendations (2)

For small runs, utilize “batch” strategy

QC at beginning

QC at end

Release results after inspect all controls and reviewing patient results when necessary

What frequency of QC? Recommendations (3)

For large runs, highly automated systems with continuous reporting of results

Controls at beginning of run

Right QC design to detect medically important errors

+ Controls for events

e.g., Change of reagent lots

+ Controls to monitor performance during run

Or, possibly use mean or median of patient data to monitor stability during run

+ Controls at end of run

How important are the manufacturer’s QC directions?

Recommendations (4)

Provide minimum requirements that the laboratory must satisfy

E.g., calibration, preventive maintenance, etc.

Laboratory is still responsible for design of IQC system

Intended clinical use

Observed method performance

Necessary QC rules and Numbers of measurements

How important manufacturers QC directions? Recommendations (5)

Need for “independent” control

“Third party control

Traceability is an important responsibility of manufacturer

Calibration materials and process

Verification/validation of method performance is an important responsibility of the laboratory

EQA/PT important responsibility in monitoring/measuring accuracy over time

“Commutability” important characteristic of materials

How often EQA/PT? Recommendations (6)

At least monthly

With fast turnaround of results to be useful for identifying bias and making improvements in the laboratory

Approved EQA program preferred

ILAC G13:08/2007

ISO 17043

Most essential information – bias observed vs “assigned value”

Other issues of interest

Medical relevance

“Intended use,” “intended quality of test results”

Traceability

Comparability of test results

Validation of method performance

Design of IQC

Available planning approach, tools

How assure quality?

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(3) Validate MethodPerformance (CV,bias)

(1) Define Goals for Intended Use

(TEa, Dint)

(3a) Manufacturer’sClaims

(1a) Regulatory &AccreditationRequirements

(1b) Clinical and Medical Applications

(2) Select AnalyticMeasurement

Procedure

(2a) Traceability& Calibration

(2b) Manufacturer’sReference Methods

& Materials

(4) Design SQC(rules, N, F)

(5) FormulateAQC Strategy

(11) Improve AQCEffectiveness

(5b) Lab Evaluationof Residual Risk

(5a) Manufacturer’sRisk Analysis

(6) Develop AQC Plan

(10) Monitor AQCEffectiveness (f), EQA

(7) Implement AQC System

(6a) QC Toolbox

(8) Verify Attainmentof Intended Quality

of Test Results

(9) Measure Quality& Uncertainty

ISO 15198 ISO 15198 Validation of QC ProceduresValidation of QC Procedures

QC procedures shall be validated to assure QC procedures shall be validated to assure that failures are not a hazard to patients that failures are not a hazard to patients

Recommends use of risk analysisRecommends use of risk analysis

Conventional statistical quality control Conventional statistical quality control procedures (e.g., as described in CLSI procedures (e.g., as described in CLSI C24) are considered adequateC24) are considered adequate

Validation may be based on simulated effects Validation may be based on simulated effects of errors on performance dataof errors on performance data

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CLSI C24 QC Planning Process

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Define quality specifications for test

Select appropriate control materials

Determine method performance

Identify quality control strategies

Predict QC performance

Specify goals for QC performance

Select QC to satisfy goals

CalculateSigma

%TEa-%Bias%CV

UtilizeSigma-metricQC Selection

Tool

SigmaSigma--metrics QC Selection Toolmetrics QC Selection Tool 2 Levels Control2 Levels Control

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0 1.0 2.0 3.0 4.0

1.65 2.65 3.65 4.65 5.65

13s/2of32s/R4s/31s/6x 0.07 ----- 6 113s/22s/R4s/41s/8x 0.03 ----- 4 213s/22s/R4s/41s 0.03 ----- 4 112.5s 0.04 ----- 4 112.5s 0.03 ----- 2 113s/22s/R4s 0.01 ----- 2 113s 0.00 ----- 2 113.5s 0.00 ----- 2 1

Pfr Ped N R

Pro

babi

lity

for

Rej

ecti

on (

P)

Systematic Error (SE, multiples of s)

Sigma Scale

DesirableError

DetectionDesirable

FalseRejection

3 4 5

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EP22, EP23 on Risk Analysis

Original purpose of CLSI project was to develop scientific approach for defining frequency of QC

Adopted “risk analysis” approach

Failure-modes and risk should provide guidance on need for control mechanisms and frequency of QC

Analytical QC Plan should be the outcome of the risk analysis process

Important Considerations in Important Considerations in Future QC SystemsFuture QC Systems

DesignDesign

Is there a scientific basis and approach for selecting Is there a scientific basis and approach for selecting parameters and setting limits on basis of parameters and setting limits on basis of intended intended quality of resultsquality of results??

ValidationValidation

Is there an objective approach for assessing the Is there an objective approach for assessing the reliability of technical and medical decisionsreliability of technical and medical decisions on on control status?control status?

ControlControl

Is there a quantitative process for monitoring and Is there a quantitative process for monitoring and verifying the verifying the attainment of intended quality of attainment of intended quality of test resultstest results??

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