Norwegian Clinical Chemistry EQA Program 12 March 2015

© Ortho-Clinical Diagnostics, Inc.

lot to lot variation in Clinical Chemistry and Immunoassay

Norwegian Clinical Chemistry EQA Program

12 March 2015

HOULLE Jean-Pierre

Scientific Specialist International

Ortho Clinical Diagnostic European Center

STRASBOURG


VITROS Analyzer MICROSLIDE

System Accuracy OverviewPerformance Assignment & Release

3/27/2015 2Ortho-Clinical

The OCD Release Laboratories:Support Fluids and Slide Manufacturing for

VITROS 250, 350, 950, DT60, Fusion 5,1, 3600, 4600, 5600 Analyzer

Systems

Ortho-Clinical Diagnostics – VITROS Analyzer System Accuracy Overview

• Sample Acquisition - Obtains Patient Samples for all test events.

• Reference Laboratory – Performs Reference Method Analysis.

• Accuracy Based Release Program – Set accuracy for Slide Master Lots.

• GEN Disposition/Assignment - Releases new lots of slides, CalDisk/ADD.

• Fluids Release – Releases the calibrator and control materials.

• Control Value Assignment – Sets the acceptable Quality Control Limits.

• Microbiology – Tests for any microbial contamination in Fluids or Reagents.

• Stability Laboratory - Confirms all products meet stability claims.

• Analyzer Maintenance – Assures instrument performance.

VITROS Analyzer MICROSLIDE

3

Accuracy Based Release Program (ABRP)

VITROS Traceable Link to Accuracy

• Goal: Enhance the verification

and setting of new coating

accuracy.

Reference-based

Master slide Lot

Accuracy Based Release Program

GEN Disposition/Value Assignment Tests

Reference

Method New Coating

Ortho-Clinical Diagnostics – VITROS Analyzer System Accuracy Overview4

Define Coating CharacteristicsUsing Statistical Test Designs (Slide Precision/Quality Control)

Slit 1, 2, 3 …..

Roll x

Roll 1

Roll 3

Roll 2

Roll x

Test

Uniformity

Width-wise

Length-wise


Release Multiple Customer LotsGEN/Value Assignment Process

• Each Coating is Compared to the

Master Lot (Check Web).New Coating (Same GEN) vs Check Web

-10.00

-8.00

-6.00

-4.00

-2.00

0.00

2.00

4.00

6.00

8.00

10.00

0.00 20.00 40.00 60.00 80.00 100.00 120.00

Conc [mg/dL]

Bia

s [

mg

/dL

] C

he

ck -

Re

fere

nce

MCL Limit

New Coating vs Check Web

New GEN Required

-10.00

-5.00

0.00

5.00

10.00

0.00 20.00 40.00 60.00 80.00 100.00 120.00

Conc [mg/dL]

Bia

s [

mg

/dL

] C

he

ck -

Re

fere

nce

MCL Limit

New Coating vs Check Web

New GEN Required after Value Assignment

-10

-5

0

5

10

0.00 20.00 40.00 60.00 80.00 100.00 120.00

Conc [mg/dL]

Bia

s [m

g/d

L]

Ch

eck -

Re

fere

nce

MCL Limit

New GEN

Required

Same GEN After Value

Assignment

6

Chemistry-specific Manufacturing Control Limits (MCL) are

used to assure consistent:

Length-wise and Width-wise Uniformity

Precision

Accuracy

Value Assignment through Patient Calibrations

ID

Vitros

Response

Reference

Value

Apply Patient

Cal

Regression to

Response

Conc. = 20*

Response + 1

Patient 1 0.1 3 3

Patient 2 0.2 5 5

Patient 3 0.3 7 7

Patient 4 0.4 9 9

Patient 5 0.5 11 11

Calibrator 1 0.15 Unknown 4



OCDUse Reference Value as Standards to predict Calibrators

Customer

Vitros

Response

Value

Assigned

Conc.

Apply

Calibrator

Regression to

Response

Conc. = 20*

Response + 1

Calibrator 1 0.15 4 4



Patient A 0.1 Unknown 3

Patient B 0.23 Unknown 5.6

Patient C 0.34 Unknown 7.8

Patient D 0.38 Unknown 8.6

Patient E 0.47 Unknown 10.4

Customer Use VITROS Cal Value as Standards to predict Patients

1. Reference Values

used on Patient

Samples to Create a

Standard Curve

4. VITROS is Calibrated

using Calibrator Values

Assigned from Patient

Calibration

ExampleExample

2. Using Patient Cal

Curve, determine

Calibrator Values

5. Patient

Results reported.


Relate Analyzer Response of Patients to Concentrations Determined by Reference Methods

Value Assignment of VITROS Calibratorsusing a Patient Calibration

Master Lot Concentration

VITROS Response

DR

Using Patients as “Knows”;

predict the Calibrator Fluids

SAVs


10© Ortho-Clinical Diagnostics, Inc.

ERROR BUDGET

This is the tool that was

originally used to evaluate

system variability.From

the error budget release

limits were derived


ERROR BUDGET

A typical error budget

contained the following

parts:


Maximum Allowable Displacement

The WFI (coating to

coating) is derived from

the maximum allowable

displacement and broken

down into five

components:


Performance Verifiers Level 1


Performance Verifiers Level 2


Example of Ca patient means


how we manage lot to lot bias

3/27/2015 16Ortho-Clinical


Vitros ECi TSH - MGCC lot 32

QC Mean: Assigned mean from calibration

MGCC (UL/LL):

MGCC limit calculated using QC curves. Input: Maximum allowable bias, n = 20 and

risk to customer of 10%

Max Bias (UL/LL):

Product specific maximum allowable bias (total mean bias)

Mean (n=4):

Single stability time point limit for valid time point (determined using the specific

error budget and n = 4)

IGCC (n=1):

Individual assay limit for all assay replicates

B

C

D

Maximum permitted positive bias lot to lot from the calibrated control mean taking into consideration test error at MGCC test

Reduction from Maximum allowable (Max Bias) bias using Operating Curves (n=20) to set MGCC limits

Ignore C

Maximum allowable single assay result (n=1). Data remains within the statistically accepted error.

A

10

15

20

25

30

35

40

45n

g/m

L V

itam

in D

QC Mean

MGCC UL

Max Bias UL

Mean (n=4)

IGCC (n=1)

MGCC LL

Max Bias LL

Mean (n=4)

IGCC (n=1)UL = upper limitLL = lower limit

B CD

A

Trend Warning Limits for a stability study. They are typically set to the same value as the MGCC limits (tightest limit).Performance that remains within these limits supports acceptable stability over shelf life. Exceeding these limits at a single time point requires additional review.

•Individual control results should meet the IGCC (n=1) limit to assure validity of each individual replicate and, therefore, an individual assay.•Overall mean performance should remain within the Max Bias Limits.

Slide no 19

Slope of the calibration curve (dose %CV/signal %CV)

Variation in instrument signal output within-run

Variation between well signal output

Variation in signal output due to SR (age and lot) and WR

Variation in instrument signal output between days

Current error budget structure

Variation in dose due to reading from different cal curves

Variation in dose due to using different lots of reagent

Variation in dose due to differences between labs and instruments

Slope factor

Within Machine

Well to well

Within day

Generic Reagents

Day to day variation

Within Calibration

Curve Fit (Calibration)

Within Lot

Batch to Batch

Within Lab

Lab to Lab

Total Variation3/27/2015


Vitros Eci- Calibration Quality parameters

Differences in luminometer response between

instruments, variables from the Spread Limit and signal

changes over the shelf-life of the reagents can affect the

signal of the calibrator

Example of the contribution for the TT3 assay:

Instrument to instrument 20%

Within instrument 13%

Age of the reagents - 30%

Total + 33 to - 63%


Vitros ECi- Calibration Quality Parameters

The error budget is the maximum percentage change by

which different areas of the system can vary

Example of the error budget for the TT3 assay:

Sample Metering 2.1%

Reagent Metering 1.0%

SR Metering 1.0%

SR batch to batch 3.0%

Well to well 4.0%

Incubator 0.9%

Luminometer 1.0%

Total 13%

Slide no 22

What do we use them for?Setting curve shape limits

Setting well to well limits

Setting instrument release limits

Deriving limits based on securing precisionSetting single run limits

Setting MGCC limits

Setting selling control ranges

Slope factor

Within Machine

Well to well

Within day

Generic Reagents

Day to day variation

Within Calibration

Curve Fit (Calibration)

Within Lot

Batch to Batch

Within Lab

Lab to Lab

Total Variation3/27/2015

Defined using clinical need as an input

Slide no 23

MGCC/IGCC tests

• Product performance limits– Mean control bias at MGCC

– Master curve shape at MGCC

– Limits at IGCC

• Test performance limits– Individual run limits (controls and curve shape)

– Control precision limits at MGCC

3/27/2015


Manufacturing internal QC controls


Manufacturing internal QC controls


Troponin I:Typical lot to lot variation observed on Cliniqa controls

mean sd %CV

reagent lots 1771 1780 1790 1800

level 1 0.087 0.091 0.085 0.085 0.087 0.003 3.25

level 2 0.614 0.616 0.593 0.576 0.600 0.019 3.16

level 3 6.66 6.67 6.52 6.36 6.55 0.15 2.22


Moving Average



Documents

Norwegian Clinical Chemistry EQA Program 12 March 2015