Leedoyeon methodvalidation

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What is Analytical What is Analytical

Method Validation ?Method Validation ?

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Validation Validation

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Validation PointValidation Point

Validation Protocol Validation Protocol

Monitoring,Monitoring,

Calibration,Calibration,

Change Control, Change Control,

Qualification Qualification

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Process Validation Prospective Validation

Ongoing Validation

Re-Validation: After change, Periodic,

Retrospective Validation

Analytical Method Validation Specificity, Linearity, Precision,

Accuracy/Recovery, Ruggedness

Cleaning Validation

Utility System Validation

Computer Validation

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ManMan

MachineMachine

MaterialMaterial

MethodMethod

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Scope of Method ValidationScope of Method Validation

Product release methodsProduct release methods

Stability indicating methodsStability indicating methods

In-Process testing methodsIn-Process testing methods

Analytical methods for cleaning validationAnalytical methods for cleaning validation

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Analytical Method Analytical Method

Identity testIdentity test Quantity testQuantity test

UV extraction coefficient, HPLC, Capillary UV extraction coefficient, HPLC, Capillary electrophoresiselectrophoresis

Purity test Purity test SDS-PAGE, HPLCSDS-PAGE, HPLC

Biological activity & PotencyBiological activity & Potency Cell-based bioassay, animal bioassayCell-based bioassay, animal bioassay

Stability testStability test

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What is Analytical Method What is Analytical Method Validation?Validation?

The Proof of MethodThe Proof of Method

How much evidence How much evidence is needed to is needed to convict?convict?

Provide the Provide the information of information of developed productsdeveloped products

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What is the purpose of Analytical Method Validation?

Identification of Sources and Quantitation Identification of Sources and Quantitation

of Potential errorsof Potential errors Determination if Method is Acceptable for Determination if Method is Acceptable for

Intended UseIntended Use Establish Proof that a Method Can be Used Establish Proof that a Method Can be Used

for Decision Makingfor Decision Making Satisfy FDA RequirementsSatisfy FDA Requirements

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What are the Benefits of What are the Benefits of

Analytical Method Validation?Analytical Method Validation?

Regulatory Compliance Regulatory Compliance

Assurance that Test data from Methods Assurance that Test data from Methods

are Reliableare Reliable

Establishment that Test Data are Establishment that Test Data are

Reproducible, Accurate, SpecificityReproducible, Accurate, Specificity……..

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What is What is notnot Analytical Method Analytical Method

Validation?Validation?

CalibrationCalibration

The Process of Performing Tests on Individual The Process of Performing Tests on Individual

System Components to Ensure Proper functionSystem Components to Ensure Proper function

System SuitabilitySystem Suitability

Test to verify the proper functioning of the Test to verify the proper functioning of the

operating system, i.e., the electronics, the operating system, i.e., the electronics, the

equipment, the specimens and the analytical equipment, the specimens and the analytical

operations.operations.

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HPLC Detector calibrationHPLC Detector calibration

Wavelength

Accuracy

Linear Range

Noise Level

Drift

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Typical System Suitability Test

Minimum Resolution of 3.0 Minimum Resolution of 3.0

between the analyte peak and between the analyte peak and

internal standard peaksinternal standard peaks

Relative Standard Deviation of Relative Standard Deviation of

replicate standard injections replicate standard injections

of not more than 2.0%of not more than 2.0%

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System Suitability

Sample

Validation

MethodAnalyst

Calibration

Pump

Detector

Injector

Data System

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Method Life CycleMethod Life Cycle

Validation

Development Optimization

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Verification vs. ValidationVerification vs. Validation

Compendial vs. Non-compendial MethodsCompendial vs. Non-compendial Methods

Compendial methods-VerificationCompendial methods-Verification

Non-compendial methods-ValidationNon-compendial methods-Validation

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Guideline for Method Guideline for Method Validation Validation

USP Chapter <1225>USP Chapter <1225> Validation of Compendial MethodsValidation of Compendial Methods

ICH GuidelinesICH Guidelines

Q2A, Text on Validation of Analytical procedures Q2A, Text on Validation of Analytical procedures

(March 1995)(March 1995)

Q2B, Validation of Analytical Procedures: Q2B, Validation of Analytical Procedures:

Methodology (May 1997)Methodology (May 1997)

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Regulatory and Compliance Regulatory and Compliance

Requirements ReviewRequirements Review

Validation of an analytical method is the process by which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical

applications USP 23 General Information <1225>

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The accuracy, sensitivity, specificity, and

reproducibility of test methods employed

by the firm shall be established and

documented. Such validation and

documentation may be accomplished in

accordance with 211.194(a)(2).

21 CFR PART 211 - CURRENT GOOD

MANUFACTURING PRACTICE FOR FINISHED

PHARMACEUTICALS

Subpart I-Laboratory Controls

211.165 Testing and release for distribution (e)

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A statement of each method used in the testing of the A statement of each method used in the testing of the

sample. The statement shall indicate the location of data sample. The statement shall indicate the location of data

that establish that the methods used in the testing of the that establish that the methods used in the testing of the

sample meet proper standards of accuracy and reliability as sample meet proper standards of accuracy and reliability as

applied to the product tested. (If the method employed is in applied to the product tested. (If the method employed is in

the current revision of the United States Pharmacopeia, the current revision of the United States Pharmacopeia,

National Formulary, Association of Official Analytical National Formulary, Association of Official Analytical

Chemists, Book of Methods,{2} or in other recognized Chemists, Book of Methods,{2} or in other recognized

standard references, or is detailed in an approved new drug standard references, or is detailed in an approved new drug

application and the referenced method is not modified, a application and the referenced method is not modified, a

statement indicating the method and reference will suffice). statement indicating the method and reference will suffice).

The suitability of all testing methods used shall be verified The suitability of all testing methods used shall be verified

under under

actual conditions of use. actual conditions of use.



PHARMACEUTICALS

Subpart J-Records and Reports

211.194 Laboratory records (a) (2)

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FDA also Proposed to add a new FDA also Proposed to add a new

subpart L to 211, entitled subpart L to 211, entitled ““ValidationValidation”” Subpart L-Validation Subpart L-Validation

Sec. 211.220 Process validation. Sec. 211.220 Process validation.

211.222 Methods validation. 211.222 Methods validation.

The accuracy, sensitivity, specificity, and The accuracy, sensitivity, specificity, and

reproducibility of test methods used by a reproducibility of test methods used by a

manufacturer shall be manufacturer shall be validated and documentedvalidated and documented. .

Such validation and documentation shall be Such validation and documentation shall be

accomplished in accordance with Sec. 211.194(a)accomplished in accordance with Sec. 211.194(a)

(2). (2). 21 CFR PART 211 - CURRENT GOOD


PHARMACEUTICALS

Subpart L-Validation

211.222 Method validation

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Methods validation means establishing,

through 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.


MANUFACTURING PRACTICE IN

MANUFACTURING, PROCESSING, PACKING,

OR HOLDING OF DRUGS

210.3 Definitions (b) (25)

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The objective of validation of an analytical The objective of validation of an analytical

procedure is to demonstrate that it is suitable procedure is to demonstrate that it is suitable

for its intended purposefor its intended purpose

ICH Guideline for Industry Q2A, Text on Validation of Analytical ProceduresMarch 1995

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In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: Specificity, Linearity, Range, Accuracy, and

Precision.

ICH Guideline for Industry Q2B, Validation of Analytical Procedures: Methodology

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Published Validation Published Validation GuidelinesGuidelines

1978 Current Good Manufacturing 1978 Current Good Manufacturing

Practices (cGMPs)Practices (cGMPs)

1987 FDA Validation Guideline1987 FDA Validation Guideline

1989 Supplement 9 to USP XXI1989 Supplement 9 to USP XXI

1994 FDA Reviewer Guidance1994 FDA Reviewer Guidance

1995 ICH Validation Definitions1995 ICH Validation Definitions

1997 ICH Validation Methodology1997 ICH Validation Methodology

1999 Supplement 10 to USP 231999 Supplement 10 to USP 23

2000 FDA Draft Validation Guidance2000 FDA Draft Validation Guidance

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TodayToday’’s Validation s Validation RequirementsRequirements

ICH/USP

GMPs(legal) FDA

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GMP Validation ParametersGMP Validation Parameters

AccuracyAccuracy

SpecificitySpecificity

SensitivitySensitivity

ReproducibilityReproducibility

21 CFR 211.165 (e)21 CFR 211.165 (e)

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FDA Validation ParametersFDA Validation Parameters

AccuracyAccuracy Precision Precision Linearity Linearity

(& Range)(& Range) SpecificitySpecificity

(& Determination Limit)(& Determination Limit) RecoveryRecovery RuggednessRuggedness

1987 FDA Guidelines1987 FDA Guidelines

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ICH/USP Validation ICH/USP Validation Requirements & Parameters Requirements & Parameters

SpecificitySpecificity LinearityLinearity RangeRange AccuracyAccuracy Precision Precision

RepeatabilityRepeatability Intermediate Intermediate

PrecisionPrecision ReproducibilityReproducibility

Limit of DetectionLimit of Detection Limit of QuantitationLimit of Quantitation

ICH

SpecificitySpecificity Linearity and RangeLinearity and Range AccuracyAccuracy Precision Precision Limit of DetectionLimit of Detection Limit of QuantitationLimit of Quantitation RuggednessRuggedness RobustnessRobustness

USP

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USP Data Elements Required USP Data Elements Required For Assay ValidationFor Assay Validation

Analytical PerformanceParameter

Assay Category

1

Assay Category 2Assay

Category 3

Quantitative

Limit Tests

Accuracy Yes Yes * *

Precision Yes Yes No Yes

Specificity Yes Yes Yes *

LOD No No Yes *

LOQ No Yes No *

Linearity Yes Yes No *

Range Yes Yes * *

Ruggedness Yes Yes Yes Yes* May be required, depending on the nature of the specific test.

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USP CategoriesUSP Categories

Category 1: Quantitation of major

components or

active ingredients

Category 2: Determination of impurities or

degradation products

Category 3: Determination of performance

characteristics

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ICH Validation Characteristics ICH Validation Characteristics vs. Type of Analytical vs. Type of Analytical

ProcedureProcedure

Type of Analytical Procedure

Identification

Impurity testing

AssayQuantitative

Limit Tests

Accuracy No Yes No Yes

Precision

Repeatability

No Yes No Yes

Interm. Prec.

No Yes No Yes

Specificity Yes Yes Yes Yes

LOD No No Yes No

LOQ No Yes No No

Linearity No Yes No Yes

Range No Yes No Yes

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How do we go about How do we go about performing an ICH Assay performing an ICH Assay

Method Validation?Method Validation?

Must Know and understand what it isMust Know and understand what it is

Must understand method validation termsMust understand method validation terms

Must design an experimental approach Must design an experimental approach

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Method Validation OverviewMethod Validation Overview

GMP/GLP ConsiderationGMP/GLP Consideration

Validation SOPValidation SOP

Validation ProtocolsValidation Protocols

Validation SpecificationsValidation Specifications

Validation SamplesValidation Samples

Validation StandardsValidation Standards

Reference StandardsReference Standards

Instrument Qualification and Instrument Qualification and

maintenancemaintenance

TrainingTraining

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How do we Know the How do we Know the expectations of the FDA?expectations of the FDA?

FDA Form 483

FDA Warning Letters

Personal Experiences

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483 Observations 483 Observations

There was no inadequate 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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483 Observations 483 Observations

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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FDA Waning LetterFDA Waning Letter

On addition to the example of modifying both compendial methods and customer supplied methods, we also observed the use of unvalidated in-house methods as well as unvalidated

modifications to in-house methods. 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. (June 2000)

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FDA Waning LetterFDA Waning Letter

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.

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.

(December 2000)

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FDA Warning LetterFDA Warning Letter

Attempts to corroborate data in the validation report with Attempts to corroborate data in the validation report with

supporting raw data in the laboratory were difficult and supporting raw data in the laboratory were difficult and

frustrating for the FDA personnel conducting the inspection.frustrating for the FDA personnel conducting the inspection.

OOS accuracy results reported by analyst 3 were never OOS accuracy results reported by analyst 3 were never

submitted in the final report. Repeat analysis performed in a submitted in the final report. Repeat analysis performed in a

different system passed specifications and these results were different system passed specifications and these results were

submitted in the report.submitted in the report.

Raw data and calculations were not checked by a second Raw data and calculations were not checked by a second

responsible individuals required by your procedures. responsible individuals required by your procedures.

Inaccurate calculations were noted in the report. (November Inaccurate calculations were noted in the report. (November

1997) 1997)

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FDA Warning LetterFDA Warning Letter

The process validation samples were assays 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. (August 2001)

Method validation for the product Sennosides is

inadequate in that the data does not assess all variables,

such as different mobile phase concentrations and

analytes, to demonstrate that the method can sustain

variance. (November 2001)

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FDA Systems Based FDA Systems Based Inspection:Inspection:

Laboratory SystemLaboratory System

Method Validation

13%Training/Qual.

4%

Stability Program 21%

InadequateRecords

27%

Controls. General35%

Feb – July 2002: 212 Inspections (US), 477 Observations

* Reference: Albinus D’ Sa, FDA, CDER Office of Compliance, from AAPS, Nov. 2002 presentation.

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GMP/GLP Aspects of ValidationGMP/GLP Aspects of Validation

21 CFR Part 58 Good Laboratory practice for

Nonclinical

Laboratory Studies

21 CFR Part 211

Current Good Manufacturing Practice

for Finished Pharmaceuticals

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21CFR 58.6321CFR 58.63

Equipment Equipment will be inspected, cleaned, and will be inspected, cleaned, and

maintainedmaintained

SOPsSOPs will be in place to describe methods, will be in place to describe methods,

materials, and schedules for maintenancematerials, and schedules for maintenance

Written recordsWritten records will be maintained of will be maintained of

inspections, maintenance, testing, and inspections, maintenance, testing, and

calibrationcalibration

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21 CFR 211.160 and 16521 CFR 211.160 and 165

Instruments, gauges, and recording

devices will be calibrated at suitable

intervals in accordance with an

established written program.

The accuracy, sensitivity, specificity,

and reproducibility of methods will be

established and documented.

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21 CFR 211.19421 CFR 211.194

Laboratory records- data is required to establish accuracy and reliability of test methods. USP, NF, AOAC methods that are used must be referenced. The suitability of all test methods must be verified under actual

conditions of use.

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What is it?

- It is your laboratory’s documented

procedure/philosophy that describes: What methods require validation Who is responsible for performing validation How much validation will be done for

different methods How the validation process will be

documented

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Why do you need it?

483 findings indicates that it is

expected

For consistency between methods,

operators, and projects

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Two options A very detailed SOP which covers everything

you need to plan, execute, report, and approve validation studies for all types of analytical

methods

or A very general SOP for guidance, with separate

detailed protocols for each different type of

method to be validated

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Content

- Purpose This document describes the procedures for validating

analytical methods in the XYZ Pharmaceutical

Company

- Scope This document applies to all analytical methods used

for release and stability testing

- Responsibilities State who will

- Prepare the validation protocol/guideline

- Review and approve the protocol

- Prepare the validation report

- Review and approve the validation report

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- Definitions Define any unique of ambiguous terms used within your company

- Compendial, selectivity/specificity, evaluation criteria, etc.

- Validation of non-compendial methods Noncompendial methods will be evaluated according to

the

current ICH/FDA guidelines

- Validation of compendial methods Compendial methods used for their intended

compendial material will be tested for sepcificity, intermediate precision,

and stability. Compendial methods used for non-compendial materials

will be validated according to the current ICH and FDA

guidelines

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- Revalidation of methods- Revalidation of methods

state your process for state your process for

- Updating validation for older productsUpdating validation for older products

- Revalidating when changes in synthesis, Revalidating when changes in synthesis,

formulation, or analytical procedure occurformulation, or analytical procedure occur

- Validation reports- Validation reports

state who is responsible for writing, state who is responsible for writing,

reviewing, approving, and archivingreviewing, approving, and archiving

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Validation ProtocolValidation Protocol

It is a description of…

How specific validation studies will be

performed for a given type of method

How results will be evaluated for

acceptability

It is an opportunity to document your

customer’s needs, and their

acceptance of your plan

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Validation ProtocolValidation Protocol

Example content:

Linearity-standard solutions will be

prepared and analyzed at 5 levels over

the range of 80 to 120% of the target

concentration. This will be performed in

triplicate.

Repeatability precision-a homogeneous

sample will be analyzed 6 times.

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Validation SpecificationValidation Specification

How good to my validation results need to

be?

Agree on the acceptance criteria

(specifications) before beginning the

validation.

Acceptance criteria should be based on

- The intended use of the method

- Sufficient experience with the method

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Validation SpecificationValidation Specification

Examples

Linearity-standard curves will have

correlation coefficients ≥ 0.99 and y-

intercept values less than 2% of the

target level response.

Repeatability precision-the test results

will have a RSD ≤ 2%.

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Key problem (If working with new

chemical entitles):

Having sufficient material to develop an

analytical method and perform validation

studies early in the development of a

drug

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For Bulk Pharmaceuticals the validation

samples should be representative of the

synthetic process Scale

Starting materials

Solvents

Product morphology

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For Drug Products the validation samples

should be representative of the

manufacturing process

Scale

Source of formulation components

Materials/Surfaces contacted

Container closure system

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Reference StandardsReference Standards

ICH states that “Well characterized

reference materials, with

documented purity, should be used

throughout the validation study.”

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Instrument Qualification and Instrument Qualification and MaintenanceMaintenance

Installation Qualification (IQ)

Operational Qualification (OQ)

Performance Qualification (PQ)

Maintenance

Log Books

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References References

‘‘Analytical Methods Validation for FDA ComplianceAnalytical Methods Validation for FDA Compliance’’ 교육교재 교육교재 The The

Center for Professional Advancement 2003. 3.12-14.Center for Professional Advancement 2003. 3.12-14. Guideline for submitting samples and analytical data for Guideline for submitting samples and analytical data for

kethods validation (Feb. 1987)kethods validation (Feb. 1987) ICH Q2AICH Q2A ICH Q2BICH Q2B 21 Code of Federal Registrations Part 210 and 21121 Code of Federal Registrations Part 210 and 211 Michael E. Swatrz and Ira S. Krull, Analytical method Michael E. Swatrz and Ira S. Krull, Analytical method

development and validation. Mrcel Dekker, Inc. New York, 1997.development and validation. Mrcel Dekker, Inc. New York, 1997. USP 23 <1225>USP 23 <1225> http://http://www.suregmp.com http://www.biosupport.com http://www.waters.comhttp://www.waters.com

Technology

Leedoyeon methodvalidation