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Handling Deviations & Unexpected Results during Method Validation

IVT – 7th Annual Method Validation at San FranciscoJuly 29th 2010

Upen Shah, B.S, MBASr. Director, Quality Management Amneal Pharmaceuticals

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Handling Deviations & Unexpected Results during Method Validation

Elements of Method Validation documents & deviationsRegulatory expectations Guidance documents of regulatory agenciesProtocol & report evaluationsFDA proposal for validation in cGMP

Handling OOS results and protocol exceptionsReview of protocols & compilation of dataReview reports - internal auditsReport findings and observationsDocumenting OOS and protocol exceptionsPreparing for and documenting Change Control

Investigations & records Factors contributing deviations followed by investigationsNotes from industryHandling investigations & CAPA’sMethod transfer failures Post validation failures & QC lifeAvoiding common pitfalls

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Validation Deviations & OOSWhat are analytical method validation &

deviations?

How are validations performed?

Protocols & Reports?

Identification & Evaluations of

deviations?

MV the Proof of Method?

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Guidance Documents for IndustryICH

Q2A Text on Validation of Analytical Procedures – March 1995Q2B Validation of Analytical Procedures: Methodology – Nov 1996

USP Chapter <1225>Validation of Compendial Methods

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21 CFR PART 211 –CGMP for Finished Pharmaceuticals

Subpart J-Records and Reports 211.194 Laboratory records (a) (2) method used in the testing meet proper standards of Accuracy and ReliabilityCurrent revision of the USP/NFAOAC or in other recognized Standard Ref.An approved New Drug Application and Suitability of methods under actual conditions

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Subpart I--Laboratory Controls

211.165 Testing and release for distributionAccuracy, Sensitivity, Specificity, and Reproducibility to be established and documented. Such validation and documentation accomplished in accordance with 211.194(a)(2)

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FDA Proposed New subpart L to 211, entitled “Validation”

Subpart L-Validation 211.222 Methods validation

The accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer shall be validated and documented. Such validation and documentation

shall be accomplished in accordance with Sec. 211.194(a)(2).

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21 CFR PART 210 - CGMP

210.3 Definitions (b) (25)Methods validation means establishing, thorough documented evidence, a high degree of assurance that an analytical method will consistently yield results that accurately reflect the quality characteristics of the product tested.

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Guideline for Method Validation

1978 Current Good Manufacturing Practices (cGMPs)

1987 FDA Validation Guideline

1989 Supplement 9 to USP XXI

1994 FDA Reviewer Guidance

1995 ICH Validation Definitions

1997 ICH Validation Methodology

1999 Supplement 10 to USP 23

2000 FDA Draft Validation Guidance

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Objective of Method Validations?

To demonstrate suitability for its intended use To design the experimental work for evaluation of appropriate validation characteristics simultaneously To provide a sound, overall knowledge of the capabilities of the analytical procedure for:

Specificity, Linearity, Range, Accuracy, and Precision

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Protocol Details and Evaluation for Deviations & OOS Validation protocol –

A written plan – how, parameters & characteristics, testing equipment & instruments, and decision points for acceptable test results

Deviations from a written protocol should be identified & evaluated thoroughly upon reviewing the data obtained during the testing

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In a case “OOS” results obtainedmeaning NOT meeting acceptance criteria

The protocol exceptions –To deal deviations & OOS results prior to final method validation report

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Performance of Validation Analytical method validation performance

should be meticulous could be tediouscost of not doing it right the first time?

Waste of time, money, and resources

The characteristics of the validations should be well understood

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Why Validate a Method?Fulfill FDA &/Or Other Regulatory RequirementsEstablish Proof of Method

Used for Decision MakingCritical Requirement in Risk Assessment and Management:

establishment of product-specific acceptance criteria & stability of APIs and FPs

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Validation criteria

Analytical Method ValidationSpecificity, Linearity, Precision, Accuracy/Recovery, Ruggedness

What are the acceptance criteria of each parameter?

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Verification vs. Validation

Compendial vs. Non-compendial Methods

Compendial methods-Verification

Non-compendial methods-Validation

Compendial Method Verification –

USP Chapter <1226>

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Which tests to Validate ?

Testing IDAssay / Quantitation / Purity /Dissolution / Content Uniformity

Could be HPLC, UV, GC etc.

Biological activity Testing product Stability

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Which Methods to Validate?

In-Process testing methods

Product Release methods

Stability indicating methods

Analytical methods for

Cleaning Validation / Verifications

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Contributing Factors of Deviations

Man ( Human factor )

Method ( Procedures )

Machine ( Lab Equip./ Instruments )

Material ( Chemicals & Reagents )

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FDA Validation Parameters1987 FDA GuidelinesAccuracyPrecision Linearity & RangeSpecificity & LOD / LOQRecoveryRuggedness

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ICH/USP Validation Parameters

SpecificityLinearity and RangeAccuracyPrecision Limit of DetectionLimit of QuantitationRuggednessRobustness

SpecificitySpecificityLinearityLinearityRangeRangeAccuracyAccuracyPrecision Precision RepeatabilityRepeatabilityIntermediate Intermediate PrecisionPrecisionReproducibilityReproducibility

Limit of DetectionLimit of DetectionLimit of QuantitationLimit of Quantitation

ICH USP

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Analytical MV OverviewGMP Consideration

Validation SOP / Protocols

Training

Specifications / Acceptance criteria

Sample preparation Ref. Standards

Instrument Qualification and Calibrations & Maintenance

Validation Reports

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SOAR - GAS PRICES!!

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Validation SOP & ProtocolsProcedure that describes:

methods requiring validation?responsibility for performing validation?How much?How documented?

Protocol:Needed in absence of a detailed SOPA specific procedure for a type of method under validationPlans, “Specifications” = acceptance criteriaData compilation & Final Report

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Data Review & DeviationsCompilation and data Review

Regulatory and Compliance Requirements Review

Experimental data compiled, reviewed &a final Report is prepared

Deviations, OOS & ExceptionsMust be noted & investigatedAny Deviations / Failures need to be identified

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Extensive Investigation ?Rigorous OOS procedures – When applicable?How Deviations issued?Investigations? Reported?& True error?

E.g : One data point of the standard curve of a linearity test is inconsistent with the other points (i.e., OOS because it fails acceptance criteria) E.g: Dilution by analyst. This should not be ignored to ensure someone doesn't use inappropriate procedures -- such as testing into compliance.

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Root cause may be revealed e.g trends, such as a high error rate

associated with particular analyst or a recurring instrument problem

CAPA considered - Analyst training or Instrument maintenance & calibration

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Case of Extensive Investigation NOT required

ExampleCoeluted peaks – during specificity

experiment ( e.g forced degradation, placebo/ matrix evaluation, analysis of known degradants/impurities ) The separation modified and the

validation restarted No extensive Investigation required

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Barr decision - QC release of drug substance and products & testing of in-process samples

Only validated release testing consideredApplicability to unvalidated methods?US v. Barr did not deal with method development/validation?Validation protocol criteria?

Based on experience gained in developing a new analytical methodAnalyst's best guess at what to expect following a

limited amount of experience with a new method

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When the results obtained do not comply:

investigation needs to be performed to determine

whether method development done was sufficient? OR whether the criterion was simply

too tight?

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Deviation & OOS Handling NotesMethod validation - a recursive process

Non-complying results means various possibilities:

method improvement OR Criterion to be changed with proper

justificationBased on these, changes may be made

through Change Control procedure, when required

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No system allows a company to openly deal with validation failuresNotes to be made:

ICH Q8–10 guidelines and the US FDA (OOS) guidance document provide regulatory flexibility Current industry practice is that risks be managed -

to the extent of validation studies executedbut not so much by actually using risk-based acceptance criteria

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Common Pitfalls:Calibration failure

In which Performing Tests on System Components to Ensure Proper FunctioningIf the instrument is not calibrated, tests are invalid

System Suitability failureS.S Tests to verify the proper functioning of the operating systemIf the system is not suitable, the tests are invalid

Untrained analyst & or reviewerData obtained are not to be considered

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FDA – OOS Guidance documentVery systematic approach for OOS investigation

Identifying & assessing the deviation/OOS result, Investigating - Lab phase Retesting, Resampling and full scale investigationAveraging, Outlier test Conclusion & CAPA

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Method Transfer FailuresValidated method when need to be transferred to QC routine lab or other site

Concept of “abbreviated” or “limited” validationIdentify the failuresTo verify the validation and transfer protocols Very systematic approach for investigationTreat failures as an OOS or OOTExplainable / logical OOSUnexplainable / illogical OOS

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Post Validation Failures & QC LifeQC daily routine worker - mostly not exposed to ValidationQC method training

an overview of the basis of the methodthe critical steps and materialsthe behavior of the method as reviewed

in the method validation report – for their usefulness in QC

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FDA references to use of the method validation along

with historical trending data by QC to ensure that the test method is

behaving as intendedWhy are these important?What are the implications?

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Method trending files to be reviewed on a routine basis by the Quality group

with reference to the validation parameters the capability of the method to

monitor?Method still behaving as intended

when the specifications were set? has there been a drift?to what could this be attributed? and how can it be addressed?

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FDA Form 483 Observations, Warning Letters & EIR’s

483 ObservationsThere was no adequate method validation specificity data to demonstrate that each method was capable of distinguishing the active ingredient from its impurities and degradation products.Specificity studies did not include the minimum stress conditions of acid and base hydrolysis, oxidation, thermal degradation and photolysis, degradation schematic for the active ingredient that identifies the major degradation products was not included for each product.

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Stress studies conducted as part of method validation do not target a minimum amount of degradation. … a standard period of two hours as commonly used for stress studies with no justification… Spreadsheets used to calculate linearity, percent recovery, and final assay results for the cleaning validation of …were not validated and the data transcribed from chromatographs to the spreadsheets were not checked for accuracy.

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Warning letters & EIR’s

A statement indicating that the method has not been validated in the particular formulation was included in the certificate of analysis for…use of this statement does not absolve…from using valid, accurate and reproducible methods.There is no assurance that qualification or maintenance of the laboratory equipment can consistently produce valid and accurate analytical results in that numerous examples of test data were invalidated due to instrument malfunction.

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Change control procedures in the laboratory failed to document test method changes to assure accurate, reliable, and reproducible results. The test method did not state whether a helix was to be used during dissolution testing. A … was reportedly used during method development, validation and daily method runs, but there is no documentation of a … being used in any of the documents.

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Attempts to corroborate data in the validation report with supporting raw data in the laboratory were difficult and frustrating for the FDA personnel conducting the inspection.OOS accuracy results reported by analyst 3 were never submitted in the final report. Repeat analysis performed in a different system passed specifications and these results were submitted in the report.Raw data and calculations were not checked by a second responsible individuals required by your procedures. Inaccurate calculations were noted in the report.

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The process validation samples were assayed using an HPLC method that had not been validated. The method validation used for both products … did not include a protocol that included specification and acceptance criteria. … The method validation was not reviewed and approved until during the current inspection. Lots of both products were released for distribution prior to completion of the method validation.

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Compendial methods not verified, no system suitability testing performed . Insufficient documentation of method validation, inadequate documentation of laboratory equipment calibration, Method validation documentation did not include appropriate data to verify that the analytical method produced accurate and reliable dataLaboratory equipment calibration was not adequately documented.

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Failure to validate changed USP standard methods, missing validation for stability indicating methods, insufficient documentation of test methods, insufficient documentation of changes, no follow-up of OOS situations, failure to release products that do not meet USP requirements, incomplete batch records

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Inadequate validation of the analytical method for detecting residual solvents in xxxx in that an unknown xxxx was determined above the limit Accuracy of the test for xxxx was determined at a higher concentration than the limit Linearity and limits of detection were determined above the limit of the test

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Extraneous HPLC peaks continuously explained to be autoinjector contamination, no further investigation

Missing acceptance criteria for validation testing

Failure to effectively train employees in laboratory operations to assure that original records are accurate, complete and in compliance with established specifications.

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FDA Systems Based Inspection:Laboratory System

- 477 Observations in a typical yearControls & General – 35%Inadequate Records – 27%Stability Program – 21%Method Validation – 13%&Training & Qualification – 4

Source – FDA, CDER Office of Compliance

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Most Common GMP Deficiencies by System Domestic Inspections by FDA

Quality -47%Laboratory -19%Production – 11%Facility & Equipment – 8%Materials – 6%Packaging & Labeling – 0%

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Important Check Points:Check whether any failures occurred in the past for similar methods?Review all the developmental work notebooks, data for such occurrences – Interview the Devp. Chemist/ AnalystsReview the protocols again – to find out the justifications for acceptance criteria.Verify all the critical characteristics for OOS & deviations.Where do we stand with Regulatory agency for OOS dealing?

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References• ‘Analytical Methods Validation for FDA Compliance’

Guideline for submitting samples and analytical data for methods validation (Feb. 1987)

• ICH Q2A

• ICH Q2B

• 21 Code of Federal Registrations Part 210 and 211

• USP – Current <1225>

• FDA 483’s & Warning Letters

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THANK YOUupen@amneal.com

Branchburg Facility131 Chambersbrook RoadBranchburg, NJ 08876908.231.1911www.amneal.com

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