webinar - real time airborne viable particle detection 2012...data to support monitoring position...

Real Time AirborneViable Particle Detection

TechnologyOverviewandApplicabilityToPharmaceuticalQualitySystems

© 2012, TSI Incorporated

OverviewIntroductionTechnologyOverviewLaserInducedFluorescenceCriticalOperationalParameters

ApplicationScenariosApplicationroadmapReal‐timeevaluationofaseptictechniquesRootcauseinvestigationsQualityriskmanagement


Introduction: The Desired State“Amaximallyefficient,agile,flexiblepharmaceuticalmanufacturingsectorthatreliablyproduceshighqualitydrugproductswithoutextensiveregulatoryoversight”

Anopportunityforalessrestrictiveregulatoryparadigmanddrivesinnovationandcontinualimprovementinmanufacturingprocesses

QbD ICH Q8(R2)

QRM ICH Q9

PQS ICH Q10

PQSICH Q10

QbDICHQ8(R2) QRM

ICH Q9

PAT

PAT


Pursuit of Faster Results:Traditional Microbial Monitoring

Process Environment

Review Levels

Above LimitBelow Limit

Sampling Incubation Results Reaction

2 - 14 Days


Pursuit of Faster Results:Lab-Based RMM

2-14 Days

Majority of RMM’s Reduce Incubation Time

8-48 hours


Pursuit of Faster Results:Real-Time Viable Particle Detection

+ BioTrak™Detector• NewcategoryofRMM• Opticalspectroscopy• LaserInducedFluorescence(LIF)

+ Real‐timeresults

Seconds


Risk Analysis

Root Cause Investigations

Segregate Product

TrainingQualification

QRM ICH Q9

CAPA

QbD ICH Q8

PAT

Environmental Monitoring in Real-Time

Real-time

viable particle

data

KnowledgeInformation

FMS

Respond in real-

time


ISO 21501-4 compliant particle counter 28.3 lpm

Three Stages of TSI’s BioTrak™ Real-Time Particle Counter

Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter

37mm Collection Filter for speciation of analyzed particles

Viability detector-Laser Induced Fluorescence


• Proven TSI AeroTrak 9510 Airborne Particle Counter Engine

• ISO 21501-4 Compliant Specification and Calibration

• Full Airborne Particle Counter Functionality

Airborne Particle Counter

Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter


Particle Concentrator

Clean air and small particles

Most particles of interest

The flow is slowed down for the viability detector using a concentrator

28.3 lpm flow is too fast viability detection


Particle Concentrator

What impact does the concentrator have on the particle transport

efficiency?

Air Samplers also have particle transport

efficiency concerns.


Laser Induced FluorescenceEx

cita

tion

Wav

elen

gth

Emission Wavelength

Laser Induced Fluorescence (LIF)

Viable cell metabolites tryptophan, NADH, and flavin’s (riboflavin) fluoresce when

excited by ultra-violet light

“Advanced Trigger Development” Jeyes et al, Lincoln Laboratory Journal Volume 17, Number 1, 2007


Laser Induced Fluorescence• Wanttodifferentiatethemicroorganismsfromthenonviableparticleswithfluorescenceproperties

• Difficulttaskevenwithfullexcitationandemissionspectruminformation

• Notpossibletoimplementfullspectroscopyinaffordableportableinstruments

• TSICollaborativedevelopmentsince1990’s

• TSIhasfundamentalsingleparticleLIFpatents*

*TSI Patents 5,701,012; 5,895,922; 6,831,279


Laser Induced Fluorescence


Viability Detector

Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter

• Patented* Laser Induced Fluorescence (LIF) Viability Detection

• TSI collaborative technology development over the past 20 years

*Patents 5,701,012; 5,895,922 and 6,831,279


Discrimination-Impact of Additional Optical Parameters

1610/18/2012© TSI Incorporated

Single Fluorescence Channel

Two Fluorescence Channels


Discrimination-Another way to visualize

1710/18/2012© TSI Incorporated

+ Algorithms are used to calculate a discrimination parameter+ Particles with a discrimination value higher than a threshold

are classified as viable+ Particles with optical signatures near the intersection have

potential to be misclassified (False Positive or False Negative)

A

B

AB

Discrimination Parameter


Discrimination

1810/18/2012© TSI IncorporatedDiscrimination Parameter

BetterDiscrimination+ Numberofanalysis

parameters+ Algorithms+ Orthogonal

measurements


Sensitivity




LIF Dual Sensitivity

+ Abilitytoadjustinstrumentresponsetoapplicationspace

“Clean” Environments• Low number of viable particles• Low number of total particles• Lower number of particles with fluorescent characteristics• Unacceptable to miss viable particles• HIGH SENSITIVITY

“Dirty” Environments• Higher number of viable particles• Higher number of total particles• Don’t want excessive false positives• Higher limit of viable particles acceptable to miss some• LOW SENSITIVITY


Collection Filter

37mm Collection Filter: Provides sample for speciation of optically analyzed particles

Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter


Real-Time Viable Particle Counting -Important Considerations+ Needtounderstandtheproduct’scapabilitiesandlimitations

• EffectivenessofLIFMeasurement‐ Discriminationcapability‐ FalsePositivesversusFalseNegatives

• Functionality‐ Easeofuse‐ Totalparticulatesizingcapability‐ Viableparticledetectioncapability‐ Dataavailability

• Particlecapturecapability• RegulatoryChallenges


Characterization of Real-Time Viable Particle Counter

+ Needstobecharacterizedwithexistingmethods

+ Comparabilitystudies:efficiencyoftheinstrumentundertestandthereferencesamplermustbeconsidered

+ Desirecorrelationtoexistingmethods


Regulatory Guidance-Challenges

Compendial Method

Rapid Method

ISO 14698-1 USP 1223, EP 5.1.6, PDA TR33

Real-Time Aerosol Viable Detection

Active Air Sampling Comparison: Equivalent or Better


Applicability+ LIFresultswillbedifferentthancurrentactivesamplerbasedresults

+Whatisthevalue?• Real–timedata• Continuousdata• Characterizationofprocesses• Trainingfeedback

+ Evolutiontoreal‐timerelease


Application Road Map“The Innovation Highway”

Vendor Validation

Comparability Studies

Operator Training

Real-time

release

Root cause Investigations

Monitoring Locations+ Zone Qualification

Validated in Process

Measurement

Immediate benefit Long term benefit

Confiden

ce in

the measuremen

t


Risk Analysis


Segregate Product

TrainingQualification

QRM ICH Q9

CAPA

QbD ICH Q8

PAT

Environmental Monitoring in Real-Time

Real-time

viable particle

data

KnowledgeInformation

FMS

Respond in real-

time


New Information: Grade C Example

Grade C Monitoring LocationIn Operation


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08:24 09:36 10:48 12:00 13:12

TCNT

#/M^3

11 AM

ParticleCountscomplianttoISO21501‐4

0.5 µm Counts

5 µm Counts


Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter


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VCNT

Viable Counts

12:30PM

Particleviabilitydetector


Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter

#/M^3


Root Cause investigations

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TCNT

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VCNT

12:30 PM11 AM

2 different conclusions…..

OR

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TCNT

RootcauseInvestigationsRoot Cause Investigations

#/M^3


Root Cause Investigations Collection Filter

Particle Counter

Viability Detector

Particle Concen-

trator

Collection filter

HEPA filter


RootCauseInvestigations

ICH Q8(R2) – Improved Process Knowledge

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The BioTrak detector high temporal resolution means you know when a microbial

excursion occurred

Leads toImproved root cause

investigations


IdentifyingMicrobiologicalContaminationSources


InvestigationToolQuickly determinethesourceofairbornemicrobiologicalcontamination“GeigerCounter“mode– UserconfigurableBeepforViablecounts



Leads to


Understanding the source of airborne microbiological contamination will help

determine the cause

Improved root cause

investigations



Leads to


Improved root cause

investigations

More effective CAPA


QualificationTool:Earlyriskbasedreleaseof(manufacturing)areas‐Supportedbyexistingmethods:resultsdayslater

ICH Q9 – Quality Risk Management

Loc 2Loc 1

Loc 3 Loc 4

Loc 5

6m

Grade B

Loc 6

6mBioTrak

Real-time OPC and

Airborne Viables

OPC Monitoring

location

Environmental Monitoring

location


RiskAnalysis:DatatosupportmonitoringpositionrationaleforSettlePlates,ActiveAirSamplingandParticleMonitoring:Monitoringlocationfinetuning

ICH Q9 – Quality Risk Management

Loc 1Loc 1

Grade BBioTrak

Real-time OPC andAirborne Viables

?OPC Monitoring

location

Environmental Monitoring

location


Training‐ ImmediatenotificationofpoorpracticeGowning

ICH Q9: Quality Risk Management


Training‐ ImmediatenotificationofpoorpracticeAseptictechnique



Training‐ ImmediatenotificationofpoorpracticePoorcleanroompractice



Innovation HighwayReal-Time Release

Vendor Validation

Comparability Studies

Operator Training

Goal

Root cause Investigations

Monitoring Locations+ Zone Qualification

Validated in Process

Measurement

Short to medium term benefit Long term benefit

Confiden

ce in

the measuremen

t


ThankYou

ContactInformation:TimRussell

[email protected]

[email protected]

webinar - real time airborne viable particle detection 2012...data to support monitoring position...

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