Developing a Risk-Based Design Space for Analytical Methods

Ying Verdi

IVT LAB WEEK EUROPE

June 2017

Partners in Health Since 1919

Term and Definitions

ATP and CQA

Risk Assessment, Design Space, and DoE

Control Strategy

Case Study

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Uncertainty, Error, and Risks

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•A parameter associated with the result of a measurement, that characterizes the dispersion of the values that could reasonably be attributed to the measurand

EURACHEM/CITAC Guide Quantifying Uncertainty in Analytical Measurement 3rd Edition, 2012

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•Uncertainty of measurement does not imply doubt about the validity of a measurement

•Knowledge of the uncertainty implies increased confidence in the validity of a measurement result

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Sample Preparation

Standard Preparation

Instrument Calibration

Analytical Measurement

Data Output(Acquisition and Processing)

Results Presentation

Manufacturing ProcessLaboratory

Sample

Test Portion

Drying & Weighing

Dispensing & Weighing

Representative

Homogeneity

IntegritySelectivity

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• Error of Measurement• Difference between an individual result and the true value of

the measurand

• Types of Error• Random Error• Systematic Error• Gross Error

EURACHEM/CITAC Guide Quantifying Uncertainty in Analytical Measurement 3rd Edition, 2012

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• Random Error (Noise)• In replicate measurements varies in an

unpredictable manner

• Systematic Error (Bias)• In replicate measurements remains

constant or varies in a predictable manner

• Gross errors• Only abandonment of the experiment

and a fresh start is an adequate cure

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Error Uncertainty

A single value A range or interval

The value of a known error can be applied as a correction to the result

The value of the uncertainty cannot be used to correct a measurement result

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DistributionRectangular (Uniform)

Triangular Normal

Shape

Most Conservative

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• Type A Method of evaluation of uncertainty by the statistical analysis of series of observations• Normal distribution

• Type B Method of evaluation of uncertainty by means other than the statistical analysis of series of observations• Rectangular distribution

• Triangular distribution

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• Accurately weigh approximately 100mg of reference standard into a 250-mL volumetric flask• Reference standard; Purity (99.46 ±0.25)

• Dissolve in water at a laboratory temperature of 20 ± 4°C

• Dilute to Volume and mix well

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Define

• Process Elements

Identify

• Error Sources

Estimate

• Individual Contributions

Combine

• Overall Uncertainty

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“ There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don't know. But there are also unknown unknowns – there are things we do not know we don't know. ”

— United States Secretary of Defense, Donald Rumsfeld

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Analytical Process

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• “The ATP is based on the understanding of the target measurement uncertainty, which is the maximum uncertainty that the data should have in order to maintain acceptable levels of confidence in data quality”

USP Stimuli articles: Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification

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• Assay: The procedure must be able to quantify [analyst] in [presence of X, Y, Z] over a range of A% to B% of the nominal concentration with an accuracy and uncertainty so that the reportable result falls within +/- C% of the true value with at least a 90% probability determined with 95% confidence

Specificity

Range

Accuracy

Precision (Repeatability, Intermediate Precision, Reproducibility)

Acceptable Risk

Acceptable Uncertainty

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Test Method

Noise Inputs Temp & Humidity Equipment Aging Analyst Day of Week Season of Year

Shift

Controllable Inputs Reagent Grade Apparatus Class Mixing Technique Materials Software Setting

Process Inputs Sample and Std Prep Test Solutions Instruments

Parameters

Process Outputs System Suitability Test Results

Other CQAs

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Analytical Procedure

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•Cause and Effect Diagram

• Failure Modes Effect Analysis (FMEA)

• Traffic Light Chart

• Flow Down Map

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• FMEA is used for identifying the critical method variables, and the impact of the variables on the CQAs of the analytical method• Evaluated variables using Probability, Detectability, and Severity

• Rank each variable’s (P), (S) and (D)

• Calculate the Risk Score (Risk Priority Number, RPN)

• Prioritize

P S D RPN

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Response 1 Response 2 Response 3 Response 4 Response 5

Buffer Conc. Low

%Organic High

Column Temp.

Wavelength

Mixing Time

Diluent Strength

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Raw Data

Filtered Std Solution

H2O

Filtering

UV Analysis Software

Disposable Syringe

Syringe Filter

Standard Solution

Glass Tube

Analytical Balance

Mixing Dissolving

Flow Cell

Result

Weighed Ref. Standard

WeighingVolumetric

FlaskReference Standard

Intermediate

Process

Softgood Raw Material

Hardgood Raw Material

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Typical DoE for Test Method:

• One Factor at a Time (OFAT)

• Screening

• Optimization

• Robustness

pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

53 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

53 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = Screening

3 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = ScreeningOrange Line = Reality

3 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = ScreeningOrange Line = RealityGreen Line = Optimization

3 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = ScreeningOrange Line = RealityGreen Line = Optimization

3 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = ScreeningOrange Line = RealityGreen Line = OptimizationRed line = Robustness Study

3 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = ScreeningOrange Line = RealityGreen Line = OptimizationRed line = Robustness Study

3 pH

Res

olu

tio

n

2 4 6

1.5

2.5

2.0

3.0

1.0

5

Blue Line = ScreeningOrange Line = RealityGreen Line = OptimizationRed line = Robustness Study

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• Start with Screening DoE• Study a large number of variables• Pareto rule (80/20 rule)• Factors

• linear (1st order) relationship

• Two levels (high vs low)

• Main effect interaction and quadratic relationship (2nd order)

•Optimization with fewer factors• Identify the method design space – best performance

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• Independent variables of a process

• Parameters or aspects of the process that we can set or change independently

• Type of Factors• Continuous vs Categorical Factors (HPLC flow rate, HPLC column, etc.)

• Controlled Factors (reagent grade, glassware class, etc.)

• Uncontrolled Factors (mother nature, instrument aging, vendors, etc.)

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• Dependent variables of a process

• The responses are the outputs of the process

• Response vs CQAs

• More than one response can be studied in a DoE

• Characteristic of response• Goal (minimize, maximize, on target)

• Limit

• Importance

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•Choose samples based on method category• Standard• Forced Degradation• Spiked • Precision

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• The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

• Working within the design space is not considered as a change

• Movement out of the design space is considered to be a change

• Design space is proposed by the applicant and is subject to regulatory assessment and approval

- (ICH Q8)

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Analytical Procedure

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• A planned set of controls, derived from current product and process understanding, that assures process performance and product quality (ICH Q10)

• Drug Product• Designed to ensure that a product of required quality will be produced consistently

• Derives from management of risk and should lead to assurance of consistent quality of product in alignment with the QTPP

• Analytical Procedure• Designed to ensure that the required performance of a analytical method will be

produced consistently

• Derived from method understanding, and aligned with ATP

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• Every analytical procedure has an associated control strategy• Overall method performance control strategy, e.g. System Suitability

• Unit operations control strategy, e.g., Buffer Conc. and pH

• Instrument operations control strategy, e.g., temperature, IQ, OQ, and PD, maintenance and calibration, etc.

• The Analytical Control Strategy plays a key role in ensuring that the ATP is realized throughout the lifecycle and also should be considered throughout the lifecycle as part of development, continual improvement, and change management (USP/PF <1220>)

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• What are the method performance criteria (ATP)

• Prior knowledge on analyst, chemicals, reagents, and procedure

• Knowledge gained during method development

• Risk Assessment for process steps and variables• Assure all critical method parameters (CMPs) are identified

• Design Space

• Knowledge gained during method validation

• Control Strategy implementation, maintenance, and updating

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Acetaminophen Tablet Assay (USP38-NF33 S2)

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Procedure:

Mobile phase Methanol and water (1:3)

Standard solution 0.01 mg/mL of USP Acetaminophen RS in Mobile phase

Sample stock solution Nominally 0.5 mg/mL of acetaminophen prepared as follows:

Weigh, and finely powder NLT 20 Tablets

Transfer 100 mg of acetaminophen from a portion of powdered

Tablets to a 200-mL volumetric flask

Add 100 mL of Mobile phase

Shake by mechanical means for 10 min

Sonicate for 5 min

Dilute with Mobile phase to volume

Sample solution Nominally 0.01 mg/mL of acetaminophen in Mobile phase from

the Sample stock solution

Pass a portion of this solution through a filter of 0.5-µm or finer

pore size, discarding the first 10 mL of the filtrate

Use the clear filtrate42

Analysis:

Mode LC

Detector UV 243 nm

Column 3.9-mm × 30-cm; packing L1

Flow rate 1.5 mL/min

Injection volume 10 µL

System suitability

Column efficiency NLT 1000 theoretical plates

Tailing factor NMT 2

Relative standard deviation NMT 2.0%

Acceptance criteria

90.0%–110.0%

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Mobile Phase/Diluent

Sample Stock Solution

Sample Analysis

Filtered Sample Solution

Mobile Phase/Diluent

Standard Solution

Glass Container

Graduate Cylinder

H2O

Mixing

Sonicator

Mechanical Shaker

Sample Tablets (n=20)

VolumetricFlask, 200mL

Balance

Dissolving/Mixing

Mortar/pestle

Filtering

AutosamplerVial

Autosampler

Software

Detector

Injector

Column

Thermo Control Unit

Disposable Syringe

Methanol

Syringe Filter

Glass Container

Graduate Cylinder

H2O

Mixing

Methanol

AutosamplerVial

Balance

Reference Standard

Dissolving/Mixing

VolumetricFlask

Sample Solution

VolumetricFlask

Pipet

Mixing

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• Factors• %Organic: 20 – 30%

• Flow Rate (mL/min): 1.3 – 1.7

• Column Temp. (°C): 25 - 45

• Grinding Technique: Coffee Grinder vs Mortar & Pestle

• Sonicating Duration (min): 5 - 20

• Sonicating Temp. (°C): 25 - 40

• Responses• Accuracy

• Precision

• Specificity

• Retention Time

• Samples• Diluent

• Placebo

• Spiked Sample

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Accuracy Precision SpecificityRentention

Time

pH Low Low Low Low

Counterion Type Low Low Low Low

Concentration Low Low Low Low

%Organic Low Low High High

Pump (Isocratic) Flow Rate Low Low Low High

Column Temp Low Low Low High

Wavelength Low Low Low Low

Sampling Rate Low Low Low Low

Draw speed Low Low Low Low

Injection Speed Low Low Low Low

Injection Volume Low Low Low Low

Grinding High High Low Low

Mixing Temperature High High Low Low

Mixing Duration High High Low Low

Diluent Strength Low Low Low Low

Filtration Low Low Low Low

Mixing Low Low Low Low

Mobile Phase

Grinding/Mixing

Filtering/Diluting

Sample

Preparation

Injector

HPLC

Conditions

Detector

Process Parameters

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Factors Critical (y/n) MODR%Organic y 20 - 30%

Flow Rate (mL/min) y 1.4 - 1.6Column Temp. (°C) n NAGrinding Technique n NA

Sonicating Duration (min) y 10 – 20 minSonicating Temp. (C) n NA

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CQA Unit operation How to control? Set-Point (Range) Reference

Retention Time

HPLC Setting%Organic

Content in MP 25% (20 - 30%) Screening DoE

Specificity HPLC Setting%Organic

Content in MP25% (20 - 30%) Screening DoE

Accuracy Sample Prep Sonication Time 10 min (10 - 20 min) Screening DoE

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