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STERILIZATION VALIDATIONSTERILIZATION VALIDATION

Presented by:

Efrat Hartog-DavidRegulatory Affairs, Qsite

Introduction

SterilizationProcess used to transform product free from viable microorganisms

MicroorganismsBacteriaVirusesFungi

Introduction

Why sterilization is needed?y

Medical device is assembled in

t ll dcontrolled environment, but may contain ymicroorganisms

Introduction

Why sterilization is needed?y

Microorganisms may cause infectionInvasive devices enter normally sterile body tissue

Introduction

Sterilization purposep p

To inactivate the microorganisms

Transform the medical device into sterile

Introduction

Inactivation of microorganisms

D value:Time required to achieve inactivation ofachieve inactivation of 90% of a population of the microorganism

funder specific conditions

Sterility

The absence of microorganisms cannot be proven

A sterility assurance level (SAL) is used to define the sterility

Sterility

Sterility Assurance Level (SAL)

Probability of a viable organism being present on a product unit after sterilizationafter sterilizationSAL of 10-6 is required by the FDA for yinvasive medical device

Sterilization methods

Moist heat

Ethylene oxide (ETO)Ethylene oxide (ETO)

Gamma radiation

ETO sterilization

Ethylene oxide (ETO)

Colorless flammable gas

Chemically reactivey

Irritating, carcinogenic, mutagenic gasg, g , g g

Alkylation reaction cause damage to DNA and y gproteins of microorganisms

ETO sterilization

ETO processing steps

Preconditioning/conditioningExposure to relative humidity and temperaturep y pEnsure uniformity of conditions

Sterilization cycleExposure to ETO gasg

AerationDissipation of remaining gases

ETO sterilization

Process parameters

Gas quantity>400mg/L

Temperaturep~45ºC

Relative humidity~35 – 80%

Exposure timeExposure time~90 – 360 minutes

ETO sterilization

AdvantagesMost product and packaging materials are compatibleRelatively low temperature process

DisadvantagesPenetration sometimes difficultResidualsLong process and release time

Gamma radiation sterilization

Gamma radiation

Electromagnetic radiation of short wavelength

High-energy photons are emitted from an isotope (Cobalt 60) so rce prod cing ioni ation thro gho t a(Cobalt 60) source producing ionization throughout a product

Cause damage to DNA and cellular structures of microorganismsmicroorganisms

Radiation dose is measured in kGy valuesRadiation dose is measured in kGy values


Gamma radiation effects on materials

BrittleColorOdorStiffnessSoftensToxicityChemical inertnessMelt temperature


AdvantagesDeep penetration powerNo residualsOnly one process parameter – timeLow temperature processp pRelease immediately after sterilization

DisadvantageNot all product and packaging materials are compatible

Sterility concerns

Sterilization validation

Documented procedure for obtaining, recording and p g, ginterpreting the results required to establish that a process will consistently yield product complying with predetermined specifications

SAL of 10-6 shall be demonstrated


Objectivesj

The sterilization process will consistently achieve sterility

The sterilization process will not have an adverse impact on the device or its packaging

ETO sterilization validation

Applicable standardspp

ANSI/AAMI/ISO 11135-1:2007 “Sterilization of health care products – Ethylene oxide -Part 1: Requirements for the development, validation and routine control of a sterilization process for medicalroutine control of a sterilization process for medical devices”

ANSI/AAMI/ISO 11135-2:2008 “Sterilization of health care products – Ethylene oxide -Part 2: Guidance on the application of ISO 11135-1”


ETO validation overview

Process and equipment characterizationProcess and equipment characterizationIQ (Installation Qualification)OQ (Operational Qualification)OQ (Operational Qualification)Product definitionPQ (Performance Qualification) – PhysicalPQ (Performance Qualification) PhysicalPQ (Performance Qualification) – MicrobiologicalDocumentationDocumentationRevalidation


IQ - Installation QualificationQ QIQ shall demonstrate that the sterilization equipment have been installed in accordance with their specification

OQ – Operational QualificationOQ shall demonstrate that the installed equipment is capable of delivering the specified process within defined tolerances


Product definition

Product familiesProduct configurationProduct and packaging materialsp g gDensityManufacturing environmentgBioburden

PCD (Product Challenge Device)


PQ - Performance Qualification

PQ shall use product or PCD to demonstrate that:

Equipment consistently operates in accordance with predetermined criteria

The process produces product that is sterile


PQ – PhysicalQ yPhysical PQ shall confirm the predetermined process parameters throughout the load, for the duration of the sterilization process

PQ - MicrobiologicalMicrobiological PQ shall confirm the effectiveness of the defined process in achieving the required SAL, for product/load combination


PQ - Physical

The physical PQ can be performed in parallel with the microbiological PQDuring sterilization process parameters are monitored:

Temperature Relative humidityPressure

Process parameters are within the required range


PQ – Microbiological

Determination of lethal rate of the sterilization process, according to one of the approaches:

Cycle calculation approachC l t th t d li i i ll 12 l d tiCycle parameters that deliver minimally 12 log reduction shall be calculated

Half cycle approach3 half cycles resulting in 6 log reduction shall be3 half cycles resulting in 6 log reduction shall be performed


PQ – Microbiological

Bioburden estimation

Validation cycles according to half cycle approachFractional cycle3 x Half cyclesFull cycle

Sterilized samples testingETO residual testing


Bioburden estimation

Population of viable microorganisms on or in the product

Test non-sterilized samples

Bioburden <100 CFU/product is considered relatively low

If bioburden > 1000 CFU/product the cleanness level of the manufacturing environment should be improvedimproved


Validation Cycles

Fractional cycle

3 x Half cyclesy

Full cycle


Biological Indicators (BI)

Test system containing 106 viable microorganisms to ensure SAL of 10-6

BI must be inserted in the most difficult location to sterilize in the product

Discs and Wires Paper StripsGl A lGlass Ampoule

Fractional cycleETO sterilization validation

Fractional cycle

Products inoculated with BIs Products

Product Sterility TestBI Sterility Test

BI product

X BIs show GROWTH If X>Y Y products show GROWTH

The BI is more resistant to the sterilization process, compared to the bioburden

ETO sterilization validationHalf cycle

Presents worst case scenario

Samples inoculated with BIs are subjected to half cycle

Following sterilization, BIs are removed from the samples and tested for BI sterility

All BIs should show NO GROWTH

ISO 11135: 3 half cycles must be run


Full cycley

One full cycle is requiredO e u cyc e s equ ed

Samples inoculated with BIs are subjected to full cycleSamples inoculated with BIs are subjected to full cycle

All BIs should show NO GROWTHAll BIs should show NO GROWTH

ETO residual testingETO residual testing


ETO residual testing

ETO is known to exhibit a number of biological effects:effects:

IrritationMutagenicityMutagenicityCarcinogenicity

ETO residual quantity is effected by productETO residual quantity is effected by product, packaging and process characteristicsThe ETO residuals should meet the acceptanceThe ETO residuals should meet the acceptance criteria according to ISO 10993-7Aeration may be prolongedAeration may be prolonged


Revalidation

Annually the status of the sterilization validation must be reviewed

Inspection of:BioburdenProduct design and packagingProcess equipment and parameters

Revalidation usually consist one half cycle and one full cycle

Gamma radiation sterilization validation

Applicable standards

ANSI/AAMI/ISO 11137-1:2006 “Sterilization of health care products – Radiation - Part 1: Requirements for development validation and routineRequirements for development, validation and routine control of a sterilization process for medical devices”

ANSI/AAMI/ISO 11137-2:2006 “Sterilization of health care products – Radiation - Part 2: Establishing the sterilization dose”

ANSI/AAMI/ISO 11137 3 2006ANSI/AAMI/ISO 11137-3:2006 Sterilization of health care products – Radiation - Part 3: Guidance on dosimetric aspectsp


Gamma radiation validation overview

Equipment characterizationEquipment characterizationIQ (Installation Qualification)OQ (Operational Qualification)OQ (Operational Qualification)Product definitionProcess definitionProcess definitionPQ (Performance Qualification)DocumentationDocumentationDose audit


P d t d fi itiProduct definition

P d t f iliProduct families

BioburdenSize of productNo. of componentsComplexity of productManufacturing environment


Process definition

Establishing the sterilization dose, according to one of the approaches:

The number of the bioburden is obtained and used t t th t ili ti dto set the sterilization dose

A t ili ti d i l t d d b t ti t dA sterilization dose is selected and substantiated


PQ

Dose mapping shall be carried out:Identify the sterilization dose accepted within each point inside the package

The dose mapping is dependent on:The dimensions and density of packaged productThe orientation of product within the package


VDMAX25 method

A bi b d h ll b 1000Average bioburden shall be ≤ 1000

Obtain samples of productSelect at least 10 products from each of 3 batches

Determine average bioburden

Obtain verification dose using Table 9 ( SO )(ISO 11137-2)


VDMAX25 method (cont.)

Perform verification dose experimentSelect 10 products from a single batchSelect 10 products from a single batchIrradiate at verification dose (±10%)Prod ct sterilit testProduct sterility test

I t t ti f ltInterpretation of results≤1 non-sterile – 25 kGy is substantiated

2 t il fi t i t=2 non-sterile – confirmatory experiment>2 non-sterile – sterilizaion dose shall be re establishedre-established


VDMAX25 method – confirmatory experimentMAX y p

Confirmatory verification dose experimentCo ato y e cat o dose e pe e tSelect 10 products from a single batchIrradiate at verification dose (±10%)Irradiate at verification dose (±10%)Product sterility test

Interpretation of resultsAll sterile – 25 kGy is substantiatedAll sterile 25 kGy is substantiated>1 non-sterile – sterilizaion dose shall be re-establishedre established


VDMAX25 method dose audit

Shall be performed quarterly

Obtain samples of productSelect at least 10 products from a single batchp g

Determine average bioburdeng

Perform verification dose experimentpSelect 10 products from a single batchIrradiate at verification dose (±10%)Irradiate at verification dose (±10%)Product sterility test


VDMAX25 method dose audit (cont.)

Interpretation of results

≤1 non-sterile – 25 kGy is substantiated=2 non-sterile – confirmatory experiment≥3, ≤6 non-sterile – augmentation of the sterilization dose≥7 non-sterile – sterilization dose shall be

bli h dre-established


VDMAX25 method dose audit – confirmatory experiment

Confirmatory verification dose experimentSelect 10 products from a single batchSelect 10 products from a single batchIrradiate at verification dose (±10%)Product sterility testProduct sterility test

Interpretation of resultsInterpretation of resultsAll sterile – 25 kGy is substantiated≥1 ≤4 non-sterile – augmentation of the sterilization≥1, ≤4 non-sterile augmentation of the sterilization dose≥5 non-sterile – sterilization dose shall be5 non sterile sterilization dose shall be re-established

Sterilization validation – additional tests

Additional tests for sterilized products

The sterilization process will not have an adverse impact on the device or its packaging:

Product functionality

Packaging integrityVisual inspectionVisual inspectionPeel testDye penetration test


M i t i i ff tiMaintaining process effectiveness

Routine monitoring of product bioburdenRoutine monitoring of product bioburden

Maintenance of the sterilization equipmentMaintenance of the sterilization equipment

Instrumentation used to monitor and control processInstrumentation used to monitor and control process parameters should be calibrated


A t f hAssessment of change

A h t i t d t k i l diA change to equipment, product, packaging, or loading pattern

Effect on effectiveness of the sterilization process

Effect on IQ, OQ or PQ validations

Documented rationale for decisions reached

Summary

Sterilization process is crucial for patient safety

Validation is required to establish that a process will consistently yield SAL of 10-6

process effectiveness must be maintained

Any change to product design or packaging shall be assessedassessed

Any questions?

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