2 validation tutorial jntu pharmacy

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BYDr. Suman PattanayakAssociate ProfessorDepartment of Pharma Analysis & QA.

Vijaya Institute of Pharmaceutical Sciences for Women

M. Pharm/ I SemAdvance Pharmaceutical Analysis

OverviewOverview

What is Validation?What is Validation?– This section will define validation and will put its meaning in terms This section will define validation and will put its meaning in terms

pertinent for a chemical engineer.pertinent for a chemical engineer.Food and Drug Administration (FDA) Food and Drug Administration (FDA) – This section will explain the role of the FDA in validation and the This section will explain the role of the FDA in validation and the

guidelines it sets forth.guidelines it sets forth.Equipment ValidationEquipment Validation– This section will explain what role unit operations equipment plays in This section will explain what role unit operations equipment plays in

validation and why that is important.validation and why that is important.Process ValidationProcess Validation– This section will explain the implications of validation in the overall This section will explain the implications of validation in the overall

manufacturing process.manufacturing process.Applications to Facility DesignApplications to Facility Design– This section will discuss considerations to facility design in light of This section will discuss considerations to facility design in light of

validation.validation.

What is Validation?What is Validation?

According to the Food and Drug Administration (FDA), the goal of According to the Food and Drug Administration (FDA), the goal of validation is to:validation is to:

“ “establish documented evidence which provides a high degree of establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality product meeting its predetermined specifications and quality attributes.”attributes.” [1][1]


What does this mean?What does this mean?– An quantitative approach is needed to prove quality, An quantitative approach is needed to prove quality,

functionality, and performance of a functionality, and performance of a pharmaceutical/biotechnological manufacturing process.pharmaceutical/biotechnological manufacturing process.

– This approach will be applied to individual pieces of equipment This approach will be applied to individual pieces of equipment as well as the manufacturing process as a whole.as well as the manufacturing process as a whole.

– Guidelines for validation are set by the FDA, but the specifics of Guidelines for validation are set by the FDA, but the specifics of validation are determined by the pharmaceutical/biotech validation are determined by the pharmaceutical/biotech company.company.


Phases of ValidationPhases of Validation– Validation is broken down into three phases:Validation is broken down into three phases:

Installation Qualification (IQ)Installation Qualification (IQ)Operational Qualification (OQ)Operational Qualification (OQ)Performance Qualification (PQ)Performance Qualification (PQ)

– These three protocols are used to define tests that will These three protocols are used to define tests that will demonstrate that the process consistently and repeatedly demonstrate that the process consistently and repeatedly

produces the desired productproduces the desired product..


Installation Qualification (IQ)Installation Qualification (IQ)– This is the first step in validation.This is the first step in validation.

– This protocol insures that the system/equipment and its This protocol insures that the system/equipment and its components are installed correctly and to the original components are installed correctly and to the original manufacturer’s specifications.manufacturer’s specifications.

– Calibration of major equipment, accessory equipment, and/or Calibration of major equipment, accessory equipment, and/or utilities should be performed in this step as well.utilities should be performed in this step as well.


Operational Qualification (OQ)Operational Qualification (OQ)– This step proceeds after the IQ has been performed.This step proceeds after the IQ has been performed.

– In the OQ, tests are performed on the critical parameters of the In the OQ, tests are performed on the critical parameters of the system/process. These are usually the independent and/or system/process. These are usually the independent and/or manipulated variables associated with the system/equipment.manipulated variables associated with the system/equipment.

– All tests’ data and measurements must be documented in order All tests’ data and measurements must be documented in order to set a baseline for the system/equipment.to set a baseline for the system/equipment.


Performance Qualification (PQ)Performance Qualification (PQ)– This is the third and final phase of validation.This is the third and final phase of validation.

– This phase tests the ability of the process to perform over long This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable. periods of time within tolerance deemed acceptable.

– PQ is performed on the manufacturing process as a whole. PQ is performed on the manufacturing process as a whole. Individual components of the system are not tested individually. Individual components of the system are not tested individually.


An example validation protocol can be seen here: An example validation protocol can be seen here: sample validation protocol..

FDAFDA

The FDA is a federal science-based law enforcement agency The FDA is a federal science-based law enforcement agency mandated to protect public health.mandated to protect public health.

The validation process is regulated by the guidelines and The validation process is regulated by the guidelines and restrictions set forth by the FDA. However, the actual validation restrictions set forth by the FDA. However, the actual validation protocol, documentation, and execution is the responsibility of the protocol, documentation, and execution is the responsibility of the manufacturer. More specifically, this is the responsibility of the manufacturer. More specifically, this is the responsibility of the engineer. engineer.

FDAFDA

Code of Federal Regulations (CFR)Code of Federal Regulations (CFR)– This is the body of regulations, created by the US government, This is the body of regulations, created by the US government,

that sets forth the guidelines pertaining to food and drugs.that sets forth the guidelines pertaining to food and drugs.

– 21 CFR Part 210 21 CFR Part 210 concerns current good manufacturing practice concerns current good manufacturing practice in manufacturing, processing, packing, or holding of drugs.in manufacturing, processing, packing, or holding of drugs.

– 21 CFR Part 211 concerns current good manufacturing practice 21 CFR Part 211 concerns current good manufacturing practice for finished pharmaceuticals for finished pharmaceuticals

FDAFDA

– 21 CFR Part 600 pertains to the safe production of biological 21 CFR Part 600 pertains to the safe production of biological derived products.derived products.

– 21 CFR Part 610 pertains to the safe distribution of biologically 21 CFR Part 610 pertains to the safe distribution of biologically derived products.derived products.

Equipment ValidationEquipment Validation

As mentioned earlier, each piece of must be validated in order to As mentioned earlier, each piece of must be validated in order to legally operate within the facility.legally operate within the facility.

The goal is to produce consistent results with minimal variation The goal is to produce consistent results with minimal variation without compromising the integrity of the product and the persons without compromising the integrity of the product and the persons operating the equipment.operating the equipment.

A plan of validation should be drafted and executed by engineers in A plan of validation should be drafted and executed by engineers in order to satisfy guidelines. The validation plan generally consists of order to satisfy guidelines. The validation plan generally consists of IQ and OQ sections.IQ and OQ sections.

Equipment ValidationEquipment Validation

Any major equipment changes after the initial validation will result in Any major equipment changes after the initial validation will result in the need for subsequent revalidation.the need for subsequent revalidation.

In the end, equipment validation will create specification ranges and In the end, equipment validation will create specification ranges and tolerances that will be applied to the normal operation of equipment.tolerances that will be applied to the normal operation of equipment.

Process ValidationProcess Validation

The manufacturing process, in addition to the individual equipment, The manufacturing process, in addition to the individual equipment, must be validated.must be validated.

The goal is to create a robust manufacturing process that The goal is to create a robust manufacturing process that consistently produces a drug product with minimal variation that consistently produces a drug product with minimal variation that adheres to quality criteria of purity, identity, and potency.adheres to quality criteria of purity, identity, and potency.

A validation plan for the manufacturing process should be drafted A validation plan for the manufacturing process should be drafted and executed by engineers in order to satisfy guidelines. The and executed by engineers in order to satisfy guidelines. The validation plan usually involves just a PQ section.validation plan usually involves just a PQ section.

Process ValidationProcess Validation

Just as equipment validation, major changes after the initial Just as equipment validation, major changes after the initial validation will result in the need for subsequent revalidation.validation will result in the need for subsequent revalidation.

In the end, process validation will ensure aIn the end, process validation will ensure a robust product that is robust product that is highly reproducible over timehighly reproducible over time..

Applications to Facility DesignApplications to Facility Design

Facilities should be designed in order to facilitate any changes that Facilities should be designed in order to facilitate any changes that may arise after initial validation.may arise after initial validation.

In the case of retrofitting, current facilities services (WFI, CIP, SIP, In the case of retrofitting, current facilities services (WFI, CIP, SIP, HVAC, etc.), equipment, and instrumentation should be assessed HVAC, etc.), equipment, and instrumentation should be assessed for revalidation. This assessment will be based on age of the for revalidation. This assessment will be based on age of the individual system and the needs of the new process. individual system and the needs of the new process.

ValidationValidation

ObjectivesObjectivesTo introduce the concepts of :To introduce the concepts of : Protocol developmentProtocol development Instrument qualificationInstrument qualification Analytical procedureAnalytical procedure Extent of validationExtent of validation Method transferMethod transfer Chemical and physical, biological, and microbiological test Chemical and physical, biological, and microbiological test

validationvalidation

Validation of analytical procedures requires: Qualified and calibrated instruments Documented methods Reliable reference standards Qualified analysts Sample integrity

Validation

Validation protocol for analytical method

Statement of purpose and scope Responsibilities Documented test method List of materials and equipment Procedure for the experiments for each parameter Statistical analysis Acceptance criteria for each performance parameter

Validation

Qualification of the instrument Make, model and maker’s manual Modifications Installation and operational qualification Calibration programs Maintenance schedules

Validation

Characteristics of analytical Characteristics of analytical procedures (1)procedures (1) AccuracyAccuracy PrecisionPrecision Repeatability Repeatability ReproducibilityReproducibility


Inaccurate &imprecise

Inaccurate butprecise

Accurate butimprecise


Relationship between accuracy and precision

Accurate AND Precise

Characteristics of analytical procedures (2)Characteristics of analytical procedures (2)

Ruggedness Ruggedness RobustnessRobustnessVariability caused by:Variability caused by:– Day-to-day variationsDay-to-day variations– Analyst-to-analystAnalyst-to-analyst– Laboratory-to-laboratoryLaboratory-to-laboratory– Instrument-to-instrumentInstrument-to-instrument– Chromatographic column-to-columnChromatographic column-to-column– Reagent kit-to-kitReagent kit-to-kit– Instability of analytical reagentsInstability of analytical reagents


Characteristics of analytical procedures (3)Characteristics of analytical procedures (3) Linearity and rangeLinearity and range SpecificitySpecificity SensitivitySensitivity Limit of detectionLimit of detection Limit of quantitationLimit of quantitation


Linearity of an analyte in a material

0.010

0.015

0.020

0.025

0.030

0.035

0.040

0.01 0.015 0.02 0.025 0.03 0.035 0.04

Reference material mg/mlCalc

ulat

ed a

naly

te in

mg/

mL Table of values

(x,y)

x y # Reference

material mg/mlCalculated

mg/ml

1 0.0100 0.0101

2 0.0150 0.0145

3 0.0200 0.0210

4 0.0250 0.0260

5 0.0300 0.0294

6 0.0400 0.0410


Linearity Statistics Linearity Statistics Intercept Intercept -0.0002-0.0002Limit of Linearity and RangeLimit of Linearity and Range 0.005 – 0.040 0.005 – 0.040

mg/mLmg/mLSlope Slope 1.02371.0237Correlation coefficientCorrelation coefficient

– Pearson Pearson 0.99780.9978– Olkin and Pratt Olkin and Pratt 0.99850.9985

Relative procedure standard Relative procedure standard deviationdeviation 3.4%3.4%


LOQ, LOD and SNRLOQ, LOD and SNR Limit of Quantitation Limit of Quantitation Limit of DetectionLimit of Detection Signal to Noise RatioSignal to Noise Ratio

noise

Peak ALOD

Peak BLOQ

Baseline


Different classes of analytical testsDifferent classes of analytical tests Class A: To establish identityClass A: To establish identity Class B: To detect and quantitate impuritiesClass B: To detect and quantitate impurities Class C: To determine quantitatively the Class C: To determine quantitatively the

concentration concentration

Class D: To assess the characteristicsClass D: To assess the characteristics


* A degree of bias may be allowed

Characteristic A B quant.

B Limit test

C D

Accuracy

X X X*

Precision X X XRobustness X X X X XLinearity and range X X XSpecificity X X X X XLimit of detection X Limit of quantitation X


Extent of validation New methods require complete validation Pharmacopoeial methods require partial validation (or

verification) Significant changes mean partial revalidation

equipment changes formula changed changed suppliers of critical reagents


Analytical method transferAnalytical method transferMethod transfer protocol and procedureMethod transfer protocol and procedure– precisionprecision– accuracyaccuracy– ruggednessruggedness

Written and approved specific test methodWritten and approved specific test methodProficiency checkProficiency checkFormal acceptance by new laboratoryFormal acceptance by new laboratory


Chemical laboratory validation requirements Chemical laboratory validation requirements (1)(1)

Balances Balances ChromatographyChromatography

– HPLC, HPTLC, GC, TLCHPLC, HPTLC, GC, TLCDissolution or disintegration apparatusDissolution or disintegration apparatusKarl Fischer moisture determinationKarl Fischer moisture determinationMelting, softening or freezing point apparatusMelting, softening or freezing point apparatusOvens, refrigerators, incubatorsOvens, refrigerators, incubators


Chemical laboratory validation requirements Chemical laboratory validation requirements (2)(2)

pH meterpH meterPolarimeter - optical rotationPolarimeter - optical rotationRefractometerRefractometerSpectrophotometer UV/Vis, IR, FTIR, Raman, AASpectrophotometer UV/Vis, IR, FTIR, Raman, AATimersTimersViscometerViscometerVolumetric equipmentVolumetric equipment



Typical validation of HPCL assay (1)Typical validation of HPCL assay (1)System suitability (performance check)System suitability (performance check)– system precisionsystem precision– column efficiency column efficiency – symmetry factorsymmetry factor– capacity factorcapacity factor


Typical validation of HPLC assay (2)Typical validation of HPLC assay (2)Method validationMethod validation

– specificity specificity – accuracy accuracy – precisionprecision– linearity linearity – robustness robustness

Biological assaysBiological assaysCan be difficult to "validate"Can be difficult to "validate"

"Validity" on a case by case basis"Validity" on a case by case basis

Strictly adhere to the Biological Testing monographs in Strictly adhere to the Biological Testing monographs in pharmacopoeiaspharmacopoeias


MicrobiologicalMicrobiological testing requiring validation testing requiring validationMicrobial limit testingMicrobial limit testing

Microbial countMicrobial count

Sterility testingSterility testing

Preservative effectiveness Preservative effectiveness testingtesting

Environmental monitoring programEnvironmental monitoring program

Biological testing Biological testing


Validation of microbial test procedures (1)Validation of microbial test procedures (1) Virtually impossible to completely validate test Virtually impossible to completely validate test

procedures for every microorganismprocedures for every microorganism

Neutralize /inactivate inhibitory substances, or diluteNeutralize /inactivate inhibitory substances, or dilute Periodic media challengePeriodic media challenge Media QCMedia QC Reliable methodsReliable methods


Validation of microbial test procedures (2)Validation of microbial test procedures (2) Incubation temperature and time Incubation temperature and time Media may not grow all microorganismsMedia may not grow all microorganisms Variations in media may affect recoveryVariations in media may affect recovery Inhibitory disinfectants or preservativesInhibitory disinfectants or preservatives

SampleSample– procedures procedures – handling, storage, transporthandling, storage, transport


Microbiological viable count method Microbiological viable count method validation (1)validation (1)

Methods Methods – pour plate / spread platepour plate / spread plate– membrane filtrationmembrane filtration– Most Probable NumberMost Probable Number

SSample sizeample sizeTest dilutionTest dilutionInoculation sizeInoculation size


Microbiological viable count method Microbiological viable count method validation (2)validation (2)

Membrane filtration conditionsMembrane filtration conditions

Incubation conditionsIncubation conditions

Acceptance criteriaAcceptance criteria


Sterility testing validation requirementsSterility testing validation requirements

Media growth promotion, sterility, pHMedia growth promotion, sterility, pH Product validation Product validation Stasis testing Stasis testing Environmental monitoringEnvironmental monitoring Negative controlsNegative controls Challenge organismsChallenge organisms


ResourcesResources

[1] www.fda.gov[1] www.fda.gov– 21 CFR Part 210: 21 CFR Part 210:

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=210&showFR=1CFRPart=210&showFR=1

– 21 CFR Part 211: 21 CFR Part 211: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1CFRPart=211&showFR=1



ResourcesResources

[2] www.validationworld.com[2] www.validationworld.com– Information concerning IQ: http://www.cqionline.com/knowledge/iq.htmlInformation concerning IQ: http://www.cqionline.com/knowledge/iq.html– Information concerning OQ: http://www.cqionline.com/knowledge/oq.htmlInformation concerning OQ: http://www.cqionline.com/knowledge/oq.html– Information concerning PQ: http://www.cqionline.com/knowledge/pq.htmlInformation concerning PQ: http://www.cqionline.com/knowledge/pq.html

[3] Patricia Stewart-Flaherty. Performance Validation. Presentation. 13 Apr. [3] Patricia Stewart-Flaherty. Performance Validation. Presentation. 13 Apr. 2003.2003.

[4] Sofer, Gail and Zabriskie, Dane W., ed. [4] Sofer, Gail and Zabriskie, Dane W., ed. Biopharmaceutical Process Biopharmaceutical Process ValidationValidation. New York: Marcel Dekker, 2000.. New York: Marcel Dekker, 2000.

[4] Avis, Kenneth E., Wagner, Carmen M., Wu, Vincent L., ed. [4] Avis, Kenneth E., Wagner, Carmen M., Wu, Vincent L., ed. Biotechnology: Quality Assurance and ValidationBiotechnology: Quality Assurance and Validation. Buffalo Grove, Illinois: . Buffalo Grove, Illinois: Interpharm Press, Inc., 1999.Interpharm Press, Inc., 1999.

ResourcesResources

[5] Carleton, Fredrick J. and Agalloco James P. ed. [5] Carleton, Fredrick J. and Agalloco James P. ed. Validation of Validation of Pharmaceutical ProcessesPharmaceutical Processes. New York: Marcel Dekker, Inc., 1999.. New York: Marcel Dekker, Inc., 1999.

Education

2 validation tutorial jntu pharmacy