integrated method development and validation dr. ludwig huber [email protected] raci...

Integrated Method Development and Validation

Dr. Ludwig Huber

[email protected]

RACI Conference - Chemical Analyses

© Copyright Ludwig Huber - LabCompliance Slide 2

Today’s Agenda• Lifecycle management of analytical

procedures: development, validation and routine use

• Using principles of Quality by Design to get most robust methods

• Defining validation parameters, acceptance criteria and test procedures

• Templates and examples for efficient and consistent documentations

FDA 2014

FDA 2013

NATA 2013


FDA Guide – Bioanalytical Method Validation

Major differences to the 2001 Guide

•Section on System Suitability testing

•Inclusion of incurred sample reanalysis

•Level of details on LBA similar to chromatographic methods

•Concentrations below the LLOQ should be reported as zeros

•Sample Analysis Reporting should include: All accepted and rejected analytical runs


FDA Guide – Analytical Method Validation

• Components of Quality by Design (QbD)

– Begin with an initial risk assessment and follow with multivariate experiments (design of experiments).

– Lifetime management

• Requires submission of method development data

– You should submit development data within the method validation section if they support the validation of the

method.

© Copyright Ludwig Huber - LabCompliance

Official Guidelines for Method Validation• ICH - Guidance for Industry - Q2 (R1)

Text and MethodologyMust be followed in US and Europe

• FDA: Analytical Procedures and Methods Validation for Drugs and Biologics (Draft, Feb 2014)

• FDA - Industry GuidanceBioanalytical Method Validation (Draft, Nov 2013)

• USP <1225>: Validation of Compendial Methods• USP <1226>: Verification of Compendial Procedures• USP <1224>: Transfer of Analytical Procedures

ICH = International Conference for HarmonizationUSP = United States Pharmacopeia

Slide 5

QbD components


Method Validation

• The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented (W-187)

• Failure to validate analytical test methods used for API for potency testing. (W-259)

• For example, your firm failed to validate the xxx compound to quantify Peak A for potency and robustness.

• Your firm has been unable to determine why the chromatographic columns of the same make and model had variability and could not provide adequate separation (W-259)

www.fdawarningletter.com

Slide 6


Method Validation Parameters for different Method Tasks (ICH Q2)

Analytical TaskIdentifi-cation

ImpurityQuantitative

Impurity Qualitative

Assay

Accuracy No yes No Yes

Precision

RepeatabilityIntermediate

Reproducibility

NoNoNo

YesYesYes

NoNoNo

YesYesYes

Specificity Yes Yes Yes Yes

Limit of detection No No Yes No

Limit of quantitation No Yes No No

Linearity No Yes No Yes

Range No Yes No Yes

Robustness Expected to be done during Method Development


Parameters and Tests (ICH Q2)

Parameter Tests (examples)

Accuracy Minimum at 3 concentrations, 3 replicates

Precision


Reproducibility

Minimum of 9 determinations over the specified rangeOver 3 days, 2 operators, 2 instruments,

Only required if testing is done in different laboratories

Specificity Prove with specific methods: HPLC, DAD, MS, dif. columns

Limit of detection Visual approach, S/N >= 3

Limit of Quantitation S/N >= 10, Standard deviation of response

Linearity Min 5 concentrations: visual, correlation coefficient (r)

Range 80 to 120% of test concentration, from linearity tests


Why Should we Change the Traditional Way

• Problems in routine use, too many failures• Developers not end-users• Low emphasis on method robustness and ruggedness• Poor knowledge on critical parameters –

– problems during method transfer• No or inadequate use of risk assessment• Invested time not very efficient


Possible Conflict of Interests• Development chemist

– Shortest time possible• Routine User / QC Director

– No problem during routine use– No out-of-specification situations

• Quality Assurance– Enough documentation for inspections

• Regulatory Affairs– Enough documentation for registration

• Finance– Lowest development and validation cost


Objectives of the New Approach

• Efforts for method development and validation should be value adding: building knowledge

• Method will work consistently within its design space

– Changing people

– Changing material (e.g., chromatographic column)

– Environment (transfer)

• Focus on critical parameters using a risk based approach

Compliance is still important !!!


What we really want

• Design a method and validation procedures to ensure that the method works for the intended routine use, independently from– Where it is being used– Who is using it– Specified instrumentation– Actual method parameters, as long as

they are in the defined operating range

Trouble free operation – transfer – With no method specific OOS results

© Copyright Ludwig Huber - LabCompliance

QbD - Background and regulatory Situation• Principles widely applied in all industries, particularly in car industry • Adopted by FDA in the 21st Century cGMP initiative

Reference: Pharmaceutical Quality for the 21st Century: A Risk-Based Approach (2003)

• Adopted by ICH in Q8: Product Development, 2005, updated in Q8 (R2), 2009

• In 2006, Merck & Co.’s Januvia became the first product.

• Starting to be adopted to analytical laboratories, e.g., used to design robustness into analytical methods with the Analytical Target Profile (ATP) concept

• 2013: FDA/EMA Q&As on method validation by QbD• 2014: New FDA method validation guide with QbD components

•

Slide 13


QbD in Laboratories: Key Applications

• Development and validation of analytical methods

– HPLC and others

• Transfer or analytical procedures

• Verification of compendial methods

• Analytical instrument qualification

• Dissolution testing

• Near Infrared Spectroscopy (NIR) method

• Water analysis


EFPIA Positioning Paper• Establishment of Analytical Target Profile (method

performance criteria, acceptance criteria)• ATP defines ‘what’ needs to be measured not ‘how’• ATP is submitted to regulatory agencies and approved

instead of an analytical procedure• Any analytical method conforming to the approved ATP can

be used• Alternative methods, e.g., new technology, can be used

through internal change control procedure

In line with FDA‘s general approach for QbD (no re-approval required as long as working in the approved design space)Also in line with the European Variation Guideline and with ICH Q8

Reference: Ermer, European Pharmaceutical Review, Vol 10, Issue 3 (2011)

EFPIA = European Federation of the Pharmaceutical Industries and Association


QbD in Laboratories – Current Situation and key ApplicationsSituation•No formal regulations or guidelines, no FDA pilot project•QbD can be used for all critical analytical quality parameters•Some laboratories are starting to adapt QbD for analytical method validation •FDA/EMA address methods in Q&As sessions and guide•EFPIA Positioning Paper

Key Applications•Development and validation of analytical methods•Method transfer, disolution testing

EFPIA = European Federation of the Pharmaceutical Industries and Association


Traditional Development & Validation of Analytical Methods

• Select preliminary method, scope & specifications

• Assure performance of equipment• Assure that operators are qualifified

Preparation

Development

Validation

Routine Operation

• Select and optimize method & parameters• Robustness testing• Define operational limits and SST • Preliminary validation experiments

• Document final acceptance criteria• Document final scope• Perform validation tests, incl. robustness

• Controlled transfer • Regular review• Controlled changes & Revalidation


Quality by Design for Analytical Methods

SpecificationsAnalytical Target Profile, Quality Target Method

Profile

Control Strategy for CMAs

System Suitability

Method Qualification

(ICH Q2)

Design Space, Method

Operational Ranges

Continuous Monitoring and ImprovementsQC Tracking

Method developmentCritical Method

Parameters and Critical Attributes, Risk

Assessment


QbD Terms in Method Development and ValidationProduct Development Method Development

Method ValidationExamples for Methods

Target product profile(TPP)

Analytical target profile (ATP)

Accurate quantitation of impurities in drugs

Quality target product profile (QTPP)

Quality target method profile (QTMP)

LOQ <0.05%, precision and accuracy at LOQ better than 15%

Critical process parameters (CPP)

Critical method parameters (CMP)

Flow rate, temperature, pH of mobile phase

Critical quality attributes(CQA)

Critical Method attributes (CMA)

Resolution, peak tailing

Proven acceptable range (PAR)

Method operational design range (MODR)

pH ± 1, col temperature ± 2


Define the Analytical Target Profile

• Method operational intent (what the method has to measure)Inputs from end-user department

– Ease of use, analysis cycle time, acceptable solvents, analysis cycle time

• Method performance characteristics, e.g., precision, accuracy, specificity, LOD/LOQ, linearity

• Acceptance criteria for method performance characteristics

• Which instruments will be used, where will the method be used (specific lab, specific site, global)?

Example (incomplete): Quantitative impurity analysis compound at ≥0.05% with an accuracy and precision of 15% RSD at the limit of quantitation and 5% at 20x LOQ.


Determine Factors Impacting Critical Method Attributes (CMA)

• Test Conditions– HPLC Mobile phase composition, pH– Column Temperature, detector wavelength– Sample extraction time

• Material attributes– Matrix, sample stability, sample solubility,

column batch– Reference standards, quality of reagents

• Environmental conditions – Humidity, room temperature, electromagnetic interference

• Random effects– Analysts, e.g., skill level, thoroughness– Timing, e.g., day and night shift– Instrument, e.g., performance, maintenance

MCA

Factor2

Factor2

Factor3

Factor3

Factor1

Factor1

Use Fishbone diagrams and risk assessment


Apply Risk Assessment to Support Defined Criticality of Method Attributes

• Identify parameters with impact on the method’s performance (Risk Identification)– Rely on subject matter experts, Brainstorming meeting– May also go back to development experiments

• Develop a prioritization matrix (Risk Evaluation)– Look at factors with highest impact on method performance– Link at specified instrument

functionality, performance and qualification – Rank, e.g., in three categories: high (3), medium (2), low (1)

• Determine risk priority numbers for individual parameters

Severity Probability Detectability Risk Number

Factor 1 3 3 2 18

Factor 2 2 1 3 6


Example Risk Prioritization Matrix

1 = low, 2= medium 3 = high impact

MethodParameter

Method Attributes

col.temp.

flow rate pH%organic

phase

UVWave-length

LOQ 1 2 1 3 2

Linearity 2 1 1 3 2

Repeatability 2 1 1 2 3

Accuracy 2 3 1 3 1

Specificity 3 1 1 3 2

Risk PriorityNumber (RPN) 10 8 5 14 10

Impact of Method Parameters on Performance

RPN ≥ 9 included in DOE study


Determine the Method Operational Design Range (MODR) through DOE

• From the „Critical Method Attribute“ exercise, select factors that based on the risk assessment will impact method performance.

• Choose levels of each factor (two or higher)

• Select range over which factors will be varied, e.g., in two level study there will be a high and low level value

– Requires good knowledge of the method

• Use the multivariate experimental design approach

• Define and perform experiments

• Perform statistical analysis of data

• Interpret the data

• Perform follow-up runs (if necessary)


Design of Experiments (DoE)

• Early DoE strategies began in 1920s• Part of QbD• Helps to understand the cause and effect relationship between input factors and output

(e.g., test parameters vs. method performance)• Most important to determine a method’s robustness• Typically implemented through simultaneously changing two or more parameters,

reducing the number of experiments• Facilitated through availability of software, e.g., Design Expert (www.statease.com),

Minitab (www.minitab.com)

•

Ludwig Huber


Simple DoE Example for HPLC Method- Impact on Selectivity -

Run #%

Org.PhasepH Col. Temp Column Flow Rate

1 -1 -1 +1 +1 +1

2 -1 +1 +1 -1 +1

3 -1 +1 -1 +1 +1

4 +1 -1 +1 -1 -1

5 +1 -1 -1 +1 -1

6 +1 +1 -1 -1 -1

-1 = 40 % ACN 4.0 25 ºC 10 cm 2.0 ml/min

+1 =60% ACN

40% Water6.0 40 ºC 20 cm 2.5 ml/min

FDA: Need sufficient statistical power to support analytical “Design Space”


Validate the Method for Intended Use

• Formally validate the method following ICH Q2 • Develop a method qualification plan• Assure that equipment is formally qualified

(specifically spelled out in the new FDA guide)• Assure that personnel is formally trained• Perform qualification experiments, including robustness

testing• Evaluate data and document results• Write a validation report


Examples for HPLC Robustness Testing• Deliberately change critical operational limits and evaluate

impact on performance: precision, accuracy• Include sample preparation and testing parameters

Sample preparation (accuracy)• Extraction time (-20% of target)• Extraction temperature (± 5 ºC)

HPLC • Col Temperature (± 3 ºC)• Mobile phase composition (± 2%) • Buffer concentration (± 2%) • Flow rate (± 0.3 mL/min) • Detection wavelength (± 1 nm) • Column Lot (quality, selectivity)

Ambient temperature/humidity

Stability of samples, standards

Define acceptable ranges !


Examples for Acceptance Criteria

Parameter Test

Accuracy 90 – 110%, 80 – 120% at specifications limit

Precision


Reproducibility

<4 % RSD (up to 15% at LOQ)<5.0 % RSD (higher at LOQ)< 6% RSD (higher at LOQ)

SpecificityPeak resolution >1.5 (related substances)

or >2 (main peak)Peak purity check with UV DAD or MS

Limit of Detection N/A

Limit of Quantitation 0.05%

Linearity visual inspection of linearity curve, r>0.9900

Range o.k. if accuracy, precision, linearity criteria are met

Quantitative Impurities in Finished Drugs


Example: Report Summary TableValidation Parameter

Measure Acceptance criteria Results

Accuracy

Recovery – Conc1

Recovery – Conc2

Recovery – Conc3

97 – 103 %

97 – 103 %

97 – 103 %

99%

100%

100%Method

PrecisionRSD ≤ 1.5 % 0.4%

Intermediate Precision

RSD ≤ 2.0 % 0.8%

Specificity Peak Resolution Factor R R for all peaks >1.5 All peaks >2.0

LinearityCorrelation Coefficient

Visual inspection of plot

≥ 0.9900

Linear response plot

0.9900

Shows linearity

Range

Correlation Coefficient

Precision at 3 concentrations

Recovery at 3 Conc.

≥ 0.9900

≤ 1.5 %

97 – 103%

0.9900

<1%

99.6%

Robustness

Column Temp. ±2 C

Mobile Phase ±2 %

Sample extraction time -20 %

Compound stability 6 days

R for all peaks >1.5


Recovery in spec.

<3% degradation


R for all l peaks >2.0

Recovery in spec

<2% degradation


Assure that the Method Remains in a State of Control

• Run system suitability tests– Select critical test parameters based on risk

assessment and design space experiments• Track quality control sample test results• Thoroughly look at OOS results, and if method

specific, implement a corrective action plan• Apply rigorous change control procedures


Change Control

•Follow change control procedure•Assess the impact of each change and perform risk assessment•Take advantage of knowledge gained during robustness testing•Evaluate if the method parameter change is within the defined and tested design space and boundaries (method operational design ranges)•If not may have to revalidate the method


Coninually monitor and improve the Method

• Actively collect inputs from operators on reliability and performance of the method

• Evaluate customer complaints• Conduct regular method review, e.g., yearly• Track and trend system suitability • Respond to adverse trends before they become problems• Continually improvement through

– Problem solving and corrective action– Preventive action– Verification of correctve and preventive actions


Benefits of QbD for Laboratories- Example: Analytical Method Validation -

• Facilitates technology innovation (new technology can be used without FDA re-approval, as long as the Analytical Target Profile (ATP) is the same (future thinking)

• Technology changes can be implemented without loss of time – facilitates continuous improvement

• Less analytical method related Out-of-Specification and failure investigations

• Lower failure rates for method transfer• Allowed method changes without revalidation well defined through design

space and robustness testing

Ludwig Huber


Industry Barriers to QbD • Current guidelines not in line with QbD approaches• Registration currently not based on method performance but on method

conditions• Low motivation to change• Only little experience in the industry• Requires new tools and skills for analysts• Implementation Challenges

– Collaboration between functions – Experience with new concepts– Workload and resource limitations

Ludwig Huber


FDA-EMA Collaborative Research on QbD for Analytical Methods: Q&AsQuestion•What are the Agencies’ views with respect to the use of analytical target profile (ATP) for analytical methods?

Answer•In general, an analytical process profile (ATP) can be acceptable as a qualifier of the expected method performance by analogy to the QTPP as defined in ICH Q8 (R2). •However, the Agencies would not consider analytical methods that have different principles (e.g.,HPLC to NIR) equivalent solely on the basis of conformance with the ATP. An applicant should not switch between methods without appropriate regulatory submission and approval


FDA-EMA Collaborative Research on QbD for Analytical Methods: Q&As

Question•What are the Agencies expectations in regulatory submissions for Method Operational Design Ranges (MODR)?

Answer•For example, data to support an MODR could include: (a) appropriately chosen experimental protocols to support the proposed operating ranges/ conditions; and (b) demonstration of statistical confidence throughout the MODR.•Issues for further reflection include the assessment of validation requirements as identified in ICH Q2(R1) throughout the MODR and confirmation of system suitability across all areas of the MODR

integrated method development and validation dr. ludwig huber [email protected] raci...

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