Chiral Capillary Electrophoresis...Title Chiral Capillary Electrophoresis.pdf Author cari Created Date 10/6/2017 3:40:39 PM

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AQbD and CE

Speeding up or slowing down?

Cari Sänger van de Griend, PhDKantisto BV, the NetherlandsUppsala University, Sweden

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AQbD & CE speeding up or slowing down?

Salvador Dali, The persistence of memory, 1931, wikiart.org

AQbD processMethod requirements and Analytical Target Profile ATPTechnology selectionCritical Method Parameters CPMsMethod DevelopmentMethod ValidationMethod Application and Life Cycle Management

Concluding remarksDiscussion

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Quality by Design

From an empiric and compliance based approach towards a scientific, risk-based, holistic and proactive approach

Predefined objectives

Emphasizes product and process understanding and process control

Based on sound science and quality risk management

From ICH Q8: The degree of regulatory flexibility is predicated on the level of scientific knowledge provided.

... quality cannot be tested into products, i.e. quality should be build in by design.

This thinking can also be applied to analytical methods

AAPS PharmSciTech, Vol. 12, No. 1, March 2011

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AQbD approach

Analytical Target Profile

(ATP)

Technology selection

CriticalMethod

Parameters

Methoddevelopment

Methodvalidation

Method verification &

application

The objective and quality

requirements

Prior knowledgeMindmapCriticalityassessment

DoE: 1. Screening2. Optimization3. Robustness

Select technique(s) based on ATP

ValidateMODR

Control strategy

SSTTrendingReflection on ATP

Stage 1: Method Design, development &

Understanding

Stage 2: Method Performance

Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

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ATP

Technique selection

Criticality assessment

Method development

FMEA

Method validation


application

Analytical request (CQA)

AQbD approach

Courtesy Lars Geurink

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!AQbD is a mindset & tool to help in the process of understanding and controlling the method. AQbD is not an aim in itself! It does not replace profound knowledge of the technique and applications.

By the way, Analytical Chemistry is not an aim in itself

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AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

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Method requirements fit for purpose

Research Quality Control

The purpose of the method determines the (conscious) choices you make during method development!

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Analytical Target ProfileThe ATP states the required quality of the reportable value produced by an analytical procedure in terms of the target measurement uncertainty (TMU)

External requirements, not only from method performanceIncludes acceptable risk level evaluation TMU:

Combines uncertainty from all sourcesMaximum uncertainty associated with a reportable result while still remaining fit for intended purpose.

Examples:The procedure must be able to quantify [analyte] in the [description of test article] in the presence of [x, y, z] with the following requirements for the reportable values: Accuracy = 100% The procedure must be able to quantify [analyte] in the [description of test article] in the presence of [x, y, z] so that the reportable values fall within a TMU of C%.

Source: Stimuli to the revision process, Proposed new USP general chapter: the analytical procedure lifecycle <1220>

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Analytical Target Profile (ATP)

DefinitionThe ATP defines the objective of the test and quality requirementsfor the reportable result

10

Requester and stakeholder requirements are captured

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Method requirements

Measure product quality, not analytical uncertainty

Product Target100 %Specification

limit

Sufficient precision

Insufficient precision

Chance of improperacceptance

Specificationlimit

95% CI

Product acceptance limitsin percentage of the nominal value (%)

Total analytical methodrelative standarddeviation (% RSD)

95.0 105.0 1.9

90 100 5

85 115 10

70 130 20These numbers are for n = 3 analyses

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AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

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Choose potential technologiesPharmacopoeiasPrior knowledge and experienceExpertLiteratureFeasibility

Estimate performance on ATP requirementsIf uncertain, perform feasibility experiment

Select the best technologies for further development

(Adapted from Ambrose, Bridges, Lovett, DiPetro and Norman 2010)

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Example: Strain identity and quantification of influenza proteins

Current technique: SRIDToo low throughput: many repetitions needed to obtain sufficient precision (100 samples take 10 days)

Identification of potential techniques:

TECHNIQUE CHOIC

HPLC RP-HPLC

Analytical Target Profile (ATP) CE

CZE

CGE

cIEF

SDS-PAGESilver stain

coomassie blue stain

Product

Method to be developed

Analyte Matrix

Quality attribute of product

Type of analytical procedure

Safety QualityPotency

Quantity, identity, purity

Business requirements

Money People

EquipmentPurpose and scope

Quality control

Characterization

Time

Method requirements

Precision LOQ

AccuracySpecificityProcess

support

Validated

Range

Range

Productspecification

TargetLimits

Technique Choice

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Potential techniques: feasibility

TECHNIQUE CHOICE

HPLC RP-HPLC

Analytical Target Profile (ATP) CE

CZE

CGE

cIEF

SDS-PAGESilver stain

coomassie blue stain

Feasibility experiments

Feasibility experiments

Decision point: CGE

selected

Method Optimization

Product

Method to be developed

Analyte Matrix

Qua lity attribute of product

Type of analytical procedure

Safe ty QualityPotency

Quantity, identity, purity

Business re quireme nts

Money People

EquipmentPurpose a nd scope

Quality control

Characterization

Time

Me thod requirements

Precision LOQ

AccuracySpecificityProcess

support

Validated

Range

Range

Productspecification

TargetLimits

Talanta 144 (2015) 1030 1035

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16

AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

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Critical method parametersA list is made of method parameters per selected technique

E.g. mind map or fishbone

A criticality assessment is made for these parameters

Impact of the parameter on method performance

Certainty/uncertainty of the impact

Focusing step before risk assessments

Difference Criticality assessment Risk assessment:

Criticality assessment Risk assessment

Impact of a method parameter Impact

Certainty/uncertainty of impact Occurrence/Probability

Detectability

Focus on method only (incl. materials and instrument)

Focus on method, manpower and environment

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Method parameters mind map

Capillary Electrophoresis DS-TMD-19368

Chemicals

Sample treatment

BGE

Materials

Separation

Capillary conditioning

Applied voltage

Dilution

Benzonase treatment

Incubation temperature

Incubation time

Benzonase type

Benzonase concentration

MgCl concentration

VolumeStability

Storage

Preparation

Dissolve

Detergent

Vacuum filtration

Temperature

LightExpiration

date

PVA capillaries

Alignment interface

Capillary cassette

Flush time

Flush agent

Direction of flush

Concentration of flush agent

Tris

Tricine

Phosphoric acid

Tween80

Mili-Q

Capillary cutting

Capillary strorage

Heating instrument

Detection window

pathlength

Concentration

type

stability Concentration

type

stabilityConcentration

type

stabilityConcentratio

type

stability

Co

Fromulation buffer

Benzonase

MgCl

Pipette

technique

Range

Dileunt

MGCL type

Injectoin

Type (H,E)

Time

Energy (H,E)

Plug

Cassette temp

Sample tray temp

Capillary length

Polarity

DegassingContainer

CE instrument

Sample tray waterbath

length

way of cutting

Electrodes

Prepunchers

Pressure lines

Lifts

cleaningOperator

Environment

Authors: Ewoud van Tricht and Lars GeurinkJanssen Vaccines and PreventionContact: [email protected]

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Method parameters - fishbone

Sampling

Sample prep

Preconditioning

Dissolution

Making up to volume

HomogenizingExtraction

ReactionDilution

DenaturalizationDesalting

Stabilization

Separation

Calibration model

Stacking

BGE

Capillary

Temperature

Voltage and current

Detection

Wavelength

Bandwidth

Reference

Integration

Standards

Calibration

Number of analyses

Dependency of analyses

Sequence order

Evaluation

Rounding

Averaging

Number of decimals

Aberrant values

Out of Spec

Out of Trend

(Internal) Standards

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Criticality assessmentWhy To determine critical method parameters (CMP)

To identify method parameters of which the effect is uncertain To be able to share all CMPsTo be able to capture and re-use knowledge

How Use a mind map or fishbone to list all method parametersList down the parameters from the Mind map; list the parameters marked noiseScore on criticality by the impact of a parameter on the ATP (analysis of a sample) and the certaintyPerform feasibility experiments for parameters with low (l) certainty and significant (4) to catastrophic (5) impact until you reach high certainty

Method optimization of CMPs have priority over feasbility of pCMPsTake the CMPs along in FMEA

Who Team of 2-5 persons including at least the SME

Time Depending on experience and previous criticality assessments, a sessiontakes about 1 3 h

Discussion is good and will lead to alignmentIf discussion takes too long, take the highest value

SME = subject matter expert; FMEA = Failure mode and effect analysis; CMP = critical method parameter; pCMP = potential CMP

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Criticality assessment example

nCMP nCMP

nCMP pCMP

pCMP

pCMP

pCMP

pCMP

pCMP

CMP

CMP

CMP

CMP

CMP CMP

Certainty

High Medium Low

MDRF = method development request formCMP = critical method parameterpCMP = potential critical method parameternCMP = non-critical method parameter

IMPACT: What is the impact of the method parameter on (one of) the ATP requirements

CERTAINTY: How certain are you of the effect of the method parameter? In other words how much knowledge (data or literature or experience) do you have about this method parameter?

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22

AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

23© Kantisto BV

Risk assessmentWhy To identify critical experiments to reach ATP

To mitigate CMPs with high impact and occurrence on ATPTo be able to share all CMPs with high impact and occurrenceTo be able to capture and re-use knowledge

When Continuous updateDuring optimizing and robustness testingDuring validation and qualificationDuring troubleshooting observations from users

How List down the CMPs from the criticality assessment.Describe failure effects of the CMP on an ATP requirementScore the potential failure effect on the ATP requirement on severity/impact and probability

Use ATP priority for impact scalingHighest scores: Define mitigation and experiments, score again after the experiments

Sort the list from high to low, only mitigate the topTake some extra from the top downwards in robustness

Who Team of 2-5 persons including at least the SME

Time Depending on experience and previous RAs, a session takes about 1 3 h

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Variable Current Value

Deviation of variable orparameter from its current value orpotential failure

Potential Cause

Probability Potential Impact on Output Quality

Impact Current Detection Mode or Control Mechanism

Detectability

Follow-up Action / Mitigation StrategyResponsibility

What is the method

parameter

What can go wrong?

What are the causes

of the failure?

How bad is the effect?

How often does the failure occur?

How well understood current method

What can/will be

done?

How can this cause be found

before the analysis is

completed?

RPN = P x I X D

What is the effect on the

results?

QbD: FMEA - Failure Mode Effect Analysis

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Example FMEA Scoring

Score Impact Probability Detectibility

5 Major InvalidMeasurable impact to method performance outside of acceptable range

LikelyFailure is likely and will occur in most circumstances. Repeated failures observed (> 5%)

RemoteRemote chance that controls will detect the failure.

3 ModerateMeasurable impact to method performance that may be outside of acceptable range

OccasionalFailure is probable at some time and has been observed (1 5%)

ModerateA moderate chance that the control will detect the failure

1 MinorLittle or no measurable impact to the method performance, i.e. well within acceptable range

UnlikelyFailure could occur at some time. Only isolated incidents observed (< 1%)

HighVery likely that the control will detect the failure

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Another FMEA scoring example

Score Impact Probability

2 Negligible impact on data quality Very unlikely chance of occurrence,1/1000 reportable result

4 Minor impact on data quality Unlikely chance of occurrence,1/100 reportable result

6 Moderate impact on data quality Possible chance of occurrence,1/50 reportable result

8 Significant impact on data quality Likely chance of occurrence,1/20 reportable result

10 Strong impact on data quality Very likely chance of occurrence,1/5 reportable result

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Risk Assessment with FMEA

Impact2 4 6 8 10

Prob

abili

ty

2 4 8 12 16 20

4 8 16 24 32 40

6 12 24 36 48 60

8 16 32 48 64 80

10 20 40 60 80 100

Risk value Table (relevance x probability)Effect Value MitigationLow OptionalMedium 12 < x < 40 Recommended to mitigate if possibleHigh Must mitigate

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Failuremode effect analysis (FMEA) Example

Critical method parameters (CMP)

Potential failure effects Potential causes Severity / Impact low high (1 10)

Occurance / Probablility (1 10)

Detectability high - low (1-10)

Score (Risk priority number)

Actions/mitigations recommended

Experiments to be done Severity / Impact (1 10)




Benzonase concentration Separation

If the Benzonase concentration is too low, DNA cleavage is not complete and peaks will not be separated 8 5 2 80

Set optimal Benzonase concentration yes

Pipetting way Accuracy

When pipetting viscous solutions, fluid may remain in the tip causing a lower volume to be transported 7 8 8 448

Always rinse pipette with sample in the diluent + implement SSC concentration response 7 2 1 14

Detection wavelenght Separation

Different components absorp at different wavelenght, which could be co-eluting 8 3 2 48

Set optimal detection wavelenght yes

Detection wavelenght S/N

the analyte has certain absorption maxima, being off could lower the signal 7 1 2 14

set optimal detection wavelenght yes

Benzonase incubation temperature Separation

If the benonase inubation temperatuer is too low, DNA cleavage is not complete and peaks will not be separated 8 8 2 128

Set temperature to 37C acc material description 8 1 2 16

Benzonase incubation duration Separation

If the benzonase incubation duration is too short, DNA cleavage is not complete and peaks will not be separated. 8 5 2 80

Set incubation time to 1 h as determined for Vp-QPCR 8 3 2 48

SCORING after mitigations/actions/experiments: SCORING before mitigations/actions/experiments:

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Failuremode effect analysis (FMEA) ExampleCritical method parameters (CMP)

Potential failure effects Potential causes Severity / Impact low high (1 10)




Benzonase concentration Separation

If the Benzonase concentration is too low, DNA cleavage is not complete and peaks will not be separated 8 5 2 80

Pipetting way Accuracy

When pipetting viscous solutions, fluid may remain in the tip causing a lower volume to be transported 7 8 8 448

Detection wavelenght Separation

Different components absorp at different wavelenght, which could be co-eluting 8 3 2 48

Detection wavelenght S/N

the analyte has certain absorption maxima, being off could lower the signal 7 1 2 14

Benzonase incubation temperature Separation

If the benonase inubation temperatuer is too low, DNA cleavage is not complete and peaks will not be separated 8 8 2 128

Benzonase incubation duration Separation

If the benzonase incubation duration is too short, DNA cleavage is not complete and peaks will not be separated. 8 5 2 80

SCORING before mitigations/actions/experiments:

Actions/mitigations recommended

Experiments to be done Severity / Impact (1 10)




Set optimal Benzonase concentration yesAlways rinse pipette with sample in the diluent + implement SSC concentration response 7 2 1 14

Set optimal detection wavelenght yes

set optimal detection wavelenght yes

Set temperature to 37C acc material description 8 1 2 16

Set incubation time to 1 h as determined for Vp-QPCR 8 3 2 48

SCORING after mitigations/actions/experiments:

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AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

31© Kantisto BV

Method Development

- Good Working Practices- Design of Experiments

quadrant.org.au

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Weighing and dilution

Example: Different scenarios for making a 50 g/ml solution

Weigh 50 mg in a 100 ml volumetric flask and dilute 10 ml to 100 ml

Weigh 5 mg in a 10 ml volumetric flask and dilute 10 l to 100 l with automatic pipettes

Weigh 1 mg, dissolve in 1000 l and dilute 5 l with 95 l with automatic pipettes

= 6.3%

= 3.1%

Error values:Weighing on 5-decimal balance sw = 0.020100-ml volumetric flask sV = 0.10010-ml volumetric pipette sV = 0.020

1000- l automatic pipette sV = 3.0100- l automatic pipette sV = 0.3

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Precision of volumetric flasks and pipettes

Type Volume(ml)

Precision(ml)

Precision(% of max. volume)

Volumetric flasks 10 0.04 0.4

25 0.04 0.16

50 0.06 0.12

100 0.10 0.10

250 0.15 0.06

Volumetric pipettes 2 0.010 0.5

5 0.015 0.3

10 0.020 0.2

25 0.030 0.12

Automatic pipettes* 100 l 0.80 l 0.80

10 l 0.80 l 8.00

Graduated cylinders 500 5 1

1000 10 1*) ISO 8655 error limits for single channel pipettes, pipetting water at room temperature

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Precision of volumetric flasks and pipettes

Type Volume(ml)

Precision(ml)

Precision(% of max. volume)

Volumetric flasks 10 0.04 0.4

25 0.04 0.16

50 0.06 0.12

100 0.10 0.10

250 0.15 0.06

Volumetric pipettes 2 0.010 0.5

5 0.015 0.3

10 0.020 0.2

25 0.030 0.12

Automatic pipettes* 100 l 0.80 l 0.80

10 l 0.80 l 8.00

Graduated cylinders 500 5 1

1000 10 1*) ISO 8655 error limits for single channel pipettes green: approved for pharmaceutical analysis

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Think about how you set up your sample prep

200 µl urea-cIEF gel12 µl ampholyte20 µl cathodic stabilizer2 µl anodic stabilizer2 µl of each pI marker10 µl protein

10 µl Protein10 µl Protein

10 µl Protein

10 µl Protein10 µl Protein

10 µl Protein

Master Mix

240 µl

200 x µl urea-cIEF gel12 x µl ampholyte20 x µl cathodic stabilizer2 x µl anodic stabilizer2 x µl of each pI marker

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Method variance

So we need to be well aware of the uncertainty of every step in the method!

And take this into account

But there is more:Each technique has its own good working practices

They are different for each techniqueIt makes huge differences in accuracy, precision and robustness whether you stick to good practices or notAQbD: make very conscious selections during method development

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QbD method development starting conditionsExample

Analytep 6, unstable below pH < 5

Different and dirty matrices

BackGround Electrolyte (BGE) selection:Low-conducting buffers

High concentrations feasibleBetter buffering, potential for sample stacking, reduced electromigration dispersion, reduced adsorption

Good buffering capacityBest when pH = pKa

Tris shown to be advantageous in formulation studies

Starting point: 200 mM Tris and 200 mM tricine (pH 8.1)

Buffering co-ion and buffering counter-ionNo need to adjust pH: constant ionic strength better precisionLow conductivity higher concentrations feasible

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6-ACA buffer for CZE of mAbs

6-ACA / HAc (mM/mM) 400/25 600/35

pH 5.7 5.7

Conductivity (S/m) 0.13 0.19

Ionic strength (mM) 23 32

Buffer capacity (mM) 56 80

6-ACA, pKas 4.43 and 10.75

Calculated by PeakMaster 5.3

Popular BGE for charge heterogeneity of mAbsLow buffer capacity compensated with high concentration

High concentration possible because of low chargeAt pH 5.7: 94.4 % uncharged, 5.6 % positively charged

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Effect of BGE co-ion on EMD and peak shape

1.3 1.4 1.5 1.6 1.7 1.8 1.9 2

100 mM H3PO4 and 50 mM co-ion (pH 2.2)

Ammonium (Fastest co-ion)SodiumEthylamineDiethylamineTriethylamineTrisBisTris (Slowest co-ion)

Matching mobilities

EMD = electromigration dispersion

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Badly cut capillary: injection artefacts

1. Capillary filled with BGE

2. Capillary placed in sample vial

3. Sample injection

4. Run ongoing

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Injection practice

Increase precision, reduce carry-overBurn polyimide off capillary endsDip capillary in electrophoresis solution or water after sample injection

Removes excess sample from outside

Inject buffer/water plug after sample injectionPrevents sample loss by thermal expansion when high voltage is switched on

With or without water dip

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QbD: Good documentation

Precise BGE recipes!How?

Good example:Prepare a solution of 100 mM phosphoric acid and88 mM TRIS. Check the pH, which should be pH 3.0 0.1

Bad example:0.1 M phosphate buffer adjusted to pH 3.0 with TRIS

Why?Constant ionic strength gives better reproducibilityInfluence on EOF and electrophoretic mobilityUnambiguous recipe is easier to repeatMany buffers outside calibration range of pH-meter

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Good CE Working Practice

Capillary

Injection

Separation

DetectionQuantification

Documentation

Cleaning

Sample prep

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Method optimisation

Univariate: High risk of missing the optimum conditions

Method parameter 1univariate optimisation

Real optimum

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Design of Experiments

Experiments where parameters are tested in a multi-factorial way, that is, several parameters are varied simultaneously

Actual design depends on purpose:

Feasibility and screening

Optimization Robustness

Buffer pHTris / Tricine 8.3 +++ +++ - 0 ++Bistris / Phosphate 7.2 --Phosphate 7.0 +++ +++ + 0 +Tris HCl 7.5 0 0 -NMTP 7.2 ++6-ACA-AA 5.7 --*Borax 8.5 -^ + ++Phosphate / Tris 2.5 -

Pareto analysis

Qualitative scoring

Interaction plots Contour plots

Prediction profilers

Overall defect rate plots

Prediction profilers

Authors: Ewoud van Tricht and Lars GeurinkJanssen Vaccines and PreventionContact: [email protected]

46© Kantisto BV

Multi-factorial design

Optimization and/or Robustness testing

A B

min22 23 24 25 26 min20 21 22 23 24

0.0900.095

0.1000.105

0.110 8

9

10

1112

2

3

4

5

6

T = 30

2829

3031

32 2.90

2.95

3.00

3.053.10

2

3

4

5

6

CD = 10

Rs

C.E. Sänger van de Griend et al., J. Pharm. Biomed. Anal. 15 (1997) 1051

47© Kantisto BV

Resolution in CE

w½,1

w ½,2

t

PharmacopoeiaBUT: definition based on

Gaussian peaksOf equal height

In purity analysis, you often fulfil neither of these!

Electromigration dispersionHere

Baseline resolutionCalculated Rs = 0.7

S El Deeb, H Wätzig, D Abd El-Hady, HM Albishri, CE Sänger-van de Griend, GKE Scriba, Electrophoresis 35 (2014) 170 - 189

48© Kantisto BV

QbD Control Space / MODR

Analytical QbDMethod Operable Design Region MODR: range of operating parameters/conditions that produce correct results with acceptable precision and accuracy

Proven acceptable range

First principlesPrior knowledgeDoEModelling

Normal operating range

NOR

Unexplored space

Knowledge space

MODR

49© Kantisto BV

49

AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

50© Kantisto BV

Analytical QbD

Continuous feedback and feed forwardMeet method performance criteriaMaintain method performanceKeep the method suitable for its intended use

Production changes (scale, site, raw material, excipients)New impurities

Personnel training


Select technique

Method Development

Risk assessment

Method Validation

Control strategy

QbD lifecycle management

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Method validation a few remarksTotal error approachThe use of total error (accuracy) instead of spiked recovery (trueness) and precision: Gives the guarantee that each future measurement is included in the tolerance limits with a given risk level (typically 5%)

Eric Rozet et al. Trends in Analytical Chemistry, 30 (2011) 797-806

-expectation tolerance limits

Red line: relative bias

acceptance limit (%)

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LOD LOQ: Signal-to-Noise ratios?

S/N: variable!LOD: lowest amount that can be detectedLOQ: lowest amount that can be quantified with suitable accuracy and precisionEstimation of limit, which can be done in several ways:

Visual inspectionS/N (3:1 and 10:1)SD of response and slope (3.3 /S and 10 /S)

BlankCalibration curve

Confirm estimated limits experimentallyLevel with sufficient precision and accuracy for the intendedpurpose

0.08% (R) in (S)R.S.D.: 7.6 % (n = 6)

C.E. Sänger-van de Griend, H. Wahlström, K. Gröningsson and M. Widahl-Näsman, J. Pharm. Biomed. Anal. 15 (1997) 1051-1061

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QbD: Good documentation

Add a typical current profilePrecise rinsing descriptionsCritical method attributes

Any knowledge on critical method parameters or preparation steps and examples of successful and unsuccessful runs should be included in the method documentation If integration can be critical, also add examples of integrated electropherograms

Rune stone at Uppsala University (picture: wikipedia)

54© Kantisto BV

54

AQbD approach


(ATP)


CriticalMethod

Parameters

Methoddevelopment

Methodvalidation


application


requirements




ValidateMODR

Control strategy



Understanding


Qualification

Stage 3: Life-Cycle

Management

Riskassessment

Riskassessment

Riskassessment

55© Kantisto BV

Method transfer and life-cycle management

Implementation and life-cycle management can take 30 40% of the total time!

Use a system suitability test and control sample in each sequenceNo default SST, you know what to test for by now!

Practical training and CE courseShow good examplesShow bad examples

Monitor and trend dataReviewing of data after transfer (6 months)Check whether data remain acceptable for intended use (ATP)

We are done! Method delivered!

56© Kantisto BV

AQbD & CE Speeding up or slowing down?

There is always time to go back and do things over, but there is never time to do it right the first time

Time invested is paid back multiple times by reduced need for troubleshooting and re-analysis

patient safety

57© Kantisto BV

AQbD & CE Speeding up or slowing down?

AQbD

Systematic methodology to

ensure rightmethod at the

right time

Regulatory flexibility

(freedom to change method in design space)

Sources of variation are

understood and in control

Science

Pragmatism & realism

Control

Science

(freedom to change method in design space)

58© Kantisto BV

Quality cannot be tested into methods, quality should be build in by design!

Hadrian Wall, Northumberland, built 122 116 BC

Acknowledgements:Ewoud van TrichtLars Geurink

59© Kantisto BV

Documents

Chiral Capillary Electrophoresis...Title Chiral Capillary Electrophoresis.pdf Author cari Created Date 10/6/2017 3:40:39 PM