Jeffrey Weber Allison Scott James Drinkwater · GLP, GMP, GCP, GPvP, GDP Best Practice –risk...

Leveraging cutting‐edge Rapid Microbiological Methods to gain a comprehensive understanding of your environment and a competitive advantage

ORGANISED BY: SUPPORTED BY:

Jeffrey Weber Allison Scott James Drinkwater

RAPID MICRO METHODS FORENVIRONMENTAL MONITORING

Jeffrey W. Weber

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• Current Micro Testing • Successful RMM Platforms• Implementation guidance

Session Goals

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Current Micro Lab Testing

Water 9%

API/Raw Mtls 1%

Finished 3%

Environmental Monitoring 85%

Other 2%

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• Discrete point sampling– EM– Raw Materials– Personnel– Sterility testing

• Limited temporal information

• Retrospective– “all or nothing”– Silos

Current Micro Testing

Product

People

Process / PlantRaw

Materials

Patient

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Patient

RawMaterials

• Continuous monitoring• Holistic control• Raw material

characterization is part of process

• Extreme temporal information• Infinite sublots

• Real Time Release Testing (parametric release)

Future Micro Testing

Product

People

Process / Plant

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Patient

RawMaterials

Future RMM Platforms

Product

People

Process / Plant

Automated plate reader

Aerosol cytometry

Liquid Bioburden

Automated Water Testing

Enhanced LIMS / SPC / Cpk - MVDA

Personnel Automated Sampler

Enhanced COA data

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Manufacturing (PAT)• In‐plant testing• Raw materials screening

• Process decisions

QC (Micro Labs)• Lean labs• More automation• Less “micro” training

Who owns RMMs?

RMM

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• Investigations• Reduced in‐process inventory• Real‐time testing and near‐line, in‐process use.

• Automation advantages lab resource reduction (training or technique).–Human Error

• Special case applications are available.

RMM Benefits

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• Steve Hammond• John Ruesch• Susan Berlam• Dennis Jones• Kevin Ryan

• Mike Baumstein• Brandye Michaels• Eric Ward • Jeff Sidella• Amy McDaniel• Jerry Ryan• Michael Fenster• Manuel Selvaggio• Kerstin Andersson• Joanny Salvas

Acknowledgements

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[email protected]

James Drinkwater: PHSS Chairman – Bio‐contamination SIG Leader

Pharmaceutical and Healthcare Sciences Society ‐ PHSS.

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The development of the PHSS Bio‐contamination technical monograph

and perspective on RMM.

www.phss.co.uk

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1. Introducing the PHSS and development of the

Bio‐contamination technical monograph

www.phss.co.uk

The Pharmaceutical & Healthcare Sciences Society – PHSS are a UK based ‘Not for profit’ society, managed by qualified volunteers

operating within a defined constitution. The PHSS are developing an International profile of providing education

and training in Life sciences and best practice (GMP) via technical conferences, training courses and technical monographs that are

prepared by international special interest groups.

All publications include a regulatory review

(MHRA and if applicable FDA).

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Product Knowledge

Process Knowledge

Good PracticeGLP, GMP, GCP, GPvP, GDP

Best Practice – risk based

QbD CPVQRM PATQMS RMM

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Medicinal & Therapeutic product Life cycle

Drug Discovery

Drug &process

Development

Clinical Trial Phases

FIMT1/2/3

Marketing Authorisation

MAFormulation&

Manufacturing

Sterility & Endotoxin

Testing& Batch release

Aseptic Pharmacy

Compounding

PatientCare, Cure or Therapy

Bio‐contamination Characterisation &

profiling

Bio‐contamination

Control of classified areas

Bio‐contamination

Deviation management

Environmental monitoring of airborne & Surfaces

Chapters 1 Chapters 2 Chapters 3 Chapters 4

PHSS Bio‐contamination Technical Monograph Structure

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EU : D AISO5

B : ISO 7C : ISO8

Reducing Bio‐burden at each Barrier transition with zero (0) cfu expectation in Grade A / ISO 5. Microorganisms characterised in each controlled area as; Normal flora, Objectionable or Harmful. Characterisation through start‐up / establishing control and routine operations.

Change rooms – Step over barriers for people at room grade changes.

Disinfection Transfer hatches / Chambers for materials at barriers.

<1cfu = 0 cfu

100

50

n/a

200 cfu

•Settle plates max cfu.

•Contact plates max cfu.

•Glove prints max cfu.

•Active air cfu / cubic metre.

Total ParticlesViable &

Non viable >3520 (0.5 micron)20 (5 micron)

3520000 (0.5 µ )29000 (5 µ)

352000 (0.5 µ )2900 (5 µ)

3520000 (0.5 µ )29000 (5 µ) at Rest.

<In Operation>

Microbiological Contamination as colony forming units > (cfu)

<In Operation>

50

25

n/a

100 cfu

5

5

5

10 cfu

Bioburdenreduction at

barriers

Controlled Direct input Utilities /

services e.g. WFI & HVAC

ISO 14698

FDA guidance.

USP<797> & <1116>

Risk based GMPICH Q8/Q9/Q10

QbD – Quality by Design.

QRM ‐Quality Risk Management

3 log 4 log

6 log

3 log

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STERILISATION * 6log + penetrative process – defined in Pharmacopeias and

reference in GMP

Non penetrative surface sterilisation* residue free to prevent chemical

contamination of products.

Automated Gaseous Disinfection –High6log* & Low4log# requires qualified agents.

Required for surfaces that make direct contact with product contact surfaces. 6 log spore BI’s* used as a efficacy qualification challenge. Bench mark gaseous process: Vaporized H2O2

Environmental monitoring used to monitor impact on contamination control. Requires laboratory qualified agents.

Manual Sanitisation – A procedure using qualified agents with environmental

monitoring (EM) used to verify impact on Biocontamination control

processes validated with BI’s * 1 log reduction is 90% reduction in biological challenge population1,000000 > 100000 > 10000 > 1000 > 100 > 10 > 1 > surface sterilization.> Sterilisation (penetrative)

Required for Directproduct contact parts and surfaces

Manual Disinfection –min 4log* Grade A & 3log# all other areas: requires qualified agents.

Suitable for In‐Direct contact and non contacting surfaces. * 4 > 6 logs efficacy qualified with sporicidal challenges (BIs).

Suitable for non product contacting (direct or in‐direct) and support area surfaces. * 3 > 4 logs efficacy qualified for specified Isolates: defined as laboratory test or in zone.

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Active air, settle plates, contact

plates and swabs

Growth on plates

analysed at early stages

Fluorescence detection

systems plus RMM for ID.

Total particle monitoring and active air

response

Bio‐contamination and monitoring and Rapid Microbial Methods (RMM)

Conventional5-7 days

incubation plus ID.

RMM part growth (2 days) plus fluorescence

analysis with ID.

Real time response to

Bio-contamination detection plus ID.

Instantaneous detection of bio-contamination event. ID by others

techniques.

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Surface

samplingPassive airborne

Active

airborne

Continuous total

particles +

Real time Active air response

Real time microbial detection:

counts bfu’s –biological

fluorescing units.

Can be used with RMM Rapid Microbiological methods:

Growth and cfu count. Part Growth & Fluorescence. Fluorescence – cytometry etc.

Contact plates & swabs

Settle plates

Active air samplers Cleanroom& Isolator + D50 control of impaction.

Active air sampling activated at real time total particulate trend deviation

Continuous microbiological

event monitoring & investigations

Microbiological identification (ID) possible ID limited

Media & Incubation temperatures are important for different Microorganisms. Aerobic & Anaerobic

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A Generic version is provided in the PHSS monograph

Continuous & Viable particle monitoring

Particle Counting for Classification and Monitoring

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Lyo 1 Lyo 2

Clean Vial In feed

Buf

fer

Lyo 1 Interface Lyo 2 Interface

Cap1

Cap 2

Rapid Decon

Track & TraceEM Plates

EM sample points:C = ClassificationM= Monitoring

Fillin

g

Sample type C & M CContinuous :

Active Micro:

Settle plate : (S) Position via smoke study

Contact plates;After session / line clearance:

Real Time Micro(future): Monitor

EM sample plates : Gaseous Outer pack disinfection & contained

distribution, collection & Lab transfer

Bar-coding Track & Trace

EM Plates.

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2. PHSS Perspective of RMM

www.phss.co.uk

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1. Conventional environmental monitoring methods have poor recovery.

2. Only small (area and volume) surface and airborne samples are taken so Bio-contamination events may be missed.

3. Retrospective growth results make Root cause analysis challenging.

4. The process of sampling may introduce bio-contamination.

5. Regulatory not to exceed limits set some conventional poor recovery techniques with zero cfu expectation in Grade A / ISO 5 process zones.

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1. ID may not be possible with same technique used for monitoring real time bio-contamination events – in process.

2. RMM Lab methods are increasingly supported by validation – the challenge is handling the data in a monitoring reporting system (with all other data).

3. Bio-contamination investigations of events can be immediate giving a better chance of finding the root cause.

4. Key decisions are required on criticality of detection of bio-contamination.

5. Starting with RMM will require strategies and responses to bio-contamination based on levels of risk. This is a challenge is early comparability studies. 14

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1. Characterise ‘Base line’ of microbiological bioburden in controlled areas using conventional methods and identify / characterise microorganisms (natural, objectionable, harmful).

2. Complete ‘Comparability’ studies of Conventional and RMM techniques to be employed. Gain knowledge about the challenges / limitations and advantages.

3. Define sampling plan using RMM Lab methods and/or Real time in-process monitoring methods.

4. Correlate RMM monitoring data results against base line flora (with ID) and set initial Action and Alert levels for RMM (review periodically and reset with trend data).

5. Define investigation response to Bio-contamination RMM event: e.g. confirm as transitory event or loss of bio-contamination control.

6. Define criticality impact for detected bio-contamination e.g. impact on products and/or process.

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1. Gain knowledge about RMM before implementation. Select methods to suit process and risks.

2. Set implementation strategies for comparability studies, setting RMM Alert and Action levels and data handling / reporting.

3. Define response to RMM Bio-contamination real time events or lab results. Assess criticality of data and responses.

4. Do implement RMM in monitoring programs to support Quality by Design (QbD), Quality Risk Management (QRM) and Continuous process verification (CPV) initiatives.

5. Decide how to handle RMM data with a systematic approach (Combined EM results with cross analysis and interpretation for trend and incident rate reporting together with any necessary RCA and CAPA.

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Draft in process

Copyright © 2012 - 2013 Azbil BioVigilant, Inc.

The Advantages of Instantaneous Microbial DetectionTM Implementation

in Pharmaceutical Manufacturing

EPR WebinarMarch 2013

Allison Scott, Ph.D.Applications Engineer

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Draft in process


Need for Rapid Microbial Methods (RMMs)

• Multiple advantages– Improve speed, performance, cost, quality– Enable paradigm shift from batch to parametric release

• Regulatory encouragement/Quality initiatives– FDA encourages RMMs through the PAT and QbD initiatives for

continuous, online monitoring– EMA supports Parametric and Real Time Release with suitable critical

parameter data (e.g. environmental monitoring data)– Valuable tools for risk management and improving processes

• Overcomes traditional limitations– Standard growth-based methods are time and labor intensive,

episodic, and retrospective (e.g. 3-5 day wait)– Limited precision and sensitivity (e.g. VBNC)

USP<1223>EP 5.1.6

PDA TR33

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Draft in process


Microbial Culturabilityand Detectability

Will grow on TSA/TSB

Will NOT grow* on TSA/TSB

May Grow on TSA/TSB

*Under typical incubation conditions

“Regulatory Expectations for Aseptically Produced Parenterals”

Ian SymondsDirector Aseptic Quality AssuranceGlaxoSmithKline

December 2009, PDA Meeting, Milan, Italy

BACTERIUM Nose Pharynx MouthStaphylococcus epidermidis ++ ++ ++

Staphylococcus aureus* + + +

Streptococcus mitis + ++

Streptococcussalivarius ++ ++

Streptococcus mutans* + ++

Streptococcus pneumoniae* +/- + +

Streptococcus pyogenes + +

Neisseria sp. + ++ +

Neisseria meningitidis + ++ +

Proteus sp. + + +

Haemophilus influenzae* + + +

Lactobacillus sp. + ++

Corynebacteria ++ + +

Actinomycetes + +

Spirochetes + ++

Mycoplasmas + +

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Draft in process


RMM Detection Taxonomy

Microbial Detection

ChemicalByproduct

Spectroscopy

IntrinsicFluorescence

IntrinsicFluorescence

ExtrinsicFluorescence

Extrinsic Fluorescence

Growth/viability Independent

Growth/viability Dependent

IntrinsicRaman

Nucleic Acid

(PCR)

Spectroscopy

Azbil BioVigilant

IMD-A® Systems

MieScatter

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Draft in process


Principle of Operation

Scatter Detector

FluorescenceDetector

• Laser interrogates all particles• All particles produce Mie Scatter• Simultaneously, intrinsic fluorescence from

metabolic fluorophores is generated

Real-time operation

Immediate results

Continuous monitoring

Laser

Airflow

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Draft in process



Scatter Detector

FluorescenceDetector



Real-time operation

Immediate results


Laser

Airflow

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Draft in process





Real-time operation

Immediate results


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Draft in processEnvironmental Monitoring RMM Implementation

• Leverage manufacturer’s validation testing, IQ/OQ/PQ protocols, services, and technical support

• Utilize RMM for “non-compendial” applications:

– Investigations– Risk assessments, room

mapping– HVAC energy reduction studies– Training– Monitoring during down-time– Process improvement

Primary Validation RMM Supplier

Secondary Validation RMM End‐user

USP <1223> / EP 5.1.6 Tests • Accuracy • Precision • Linearity • Limit of Detection • Limit of Quantification • Ruggedness • Robustness • Range • Specificity Other Tests • Detection Performance • Environmental • Electrical Safety and Emissions • Software

Qualification Protocols

• Design Qualification (DQ) • Installation Qualification (IQ) • Operational Qualification (OQ) • Performance Qualification (PQ)

• Side‐by‐side testing with IMD‐A and conventional methods (i.e., currently used air samplers)

US: Type V Drug Master File submission to FDA

EU: Tests and results made available to customers

US: Review with FDAEU: Review with local inspector

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Draft in process


g-Lab AerosolChamber Test

Tested with additional facilities

Design of Experiment:

9 USP <1223> Metrics

8 Instruments

6 Microbes

5 Concentrations

12 Replicates

Example USP<1223> Validation Test Design

Microbes:– Bacillus atrophaeus– Corynebacterium

afermentans– Escherichia coli– Staphylococcus

epidermidis– Micrococcus lylae– Aspergillus niger

Instruments:– IMD-A 300 (2)– IMD-A 350 (2)– SAS, SMA, MAS– Kanomax LSAPC

g-Lab AerosolChamber Test

USP

<122

3> P

aram

eter

s

AccuracyPrecision

Detection LimitQuantification Limit

LinearityOperational Range

Specificity 1RuggednessRobustnessSpecificity 2

USP<1223> Data: Bacillus atrophaeus

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Draft in process


Powerful Tool for Investigations

• Increase likelihood of finding root cause• Reduce investigation time and costs• Increase quality assurance • Rapidly determine effectiveness of corrective

and preventive actions• Resume production faster, and with confidence

R a p i d Root-Cause Analysis

Incorrect pressure differential

Mold growing behind tiny crack in plaster

Poor seal around compressed gas conduitsHEPA filter leak

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Draft in process


HVAC Energy Reduction

• Energy costs are 2nd highest fixed cost in manufacturing (cite ref?)

• Most companies significantly exceed the minimum requirement for exchanges per hour

• Instantaneous detection of particles and microbes can be used to validate reduction of HVAC settings

• Recent customer study predicted significant energy cost savings withair exchange reduction of 25%

time

tota

l nb

of in

ert p

artic

les

Normal Reduced

time

tota

l nb

of b

iolo

gic

part

icle

s

Normal Reduced

*Manufacturing steps are not the same in the two cases**Data courtesy of Pfizer Montreal

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Draft in process

An Ideal Training Tool

• Personnel are the largest source of microbial contamination in cleanrooms (cite ref?)– Effective training programs are critical to

maintain control

• Instantaneous detection and reporting, coupled with video, provides immediate feedback for operator training on:

– Appropriate gowning

– Cleanroom behavior

– High vs. low risk operations

* Screenshots taken in cleanroom at the North Carolina BioNetwork Capstone Center at the Golden Leaf BioManufacturing Training and Education Center

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Draft in process

Monitoring of Critical PointsCritical Monitoring Point 1 -Automated bag opening in

Grade C area

Critical Monitoring Point 2 -Pass-through zone in

Grade A filling line

Comparative study performed in cooperation with IBSA Farmaceutici Italia (Lodi, Italy)

Sample Probe

IMD-A-300 System

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Draft in process


Additional RMM ApplicationsMonitoring of Controlled Areas

– Aseptic suites*– Fill lines– RABS– Isolator systems*– Safety cabinets– Compressed gasses*

Process Support– Media/water fills*– Risk assessment*

Energy reduction – green initiatives*– HVAC flow reduction studies

Investigations*– EM excursions– Root cause investigation– Verify CAPA effectiveness

Operator training*– Gowning training/qualification– Aseptic technique

Monitoring during downtime*– Routine maintenance/calibration– New construction or equipment– Equipment malfunction– Quality issue

* published literature on IMD-A system, case study data, and/or application note available

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Draft in process


Summary

• Environmental monitoring RMMs provide numerous advantages to the pharmaceutical manufacturing environment

Non-compendial• Numerous uses as a tool

in investigations, HVAC energy savings, training, etc.

• Provides visibility of RMM advantage to multiple groups within an organization

Compendial• Data-rich feedback and

software tools provide actionable process knowledge, facilitating PAT and QbD

• Instantaneous and continuous monitoring permit a more complete understanding of the environment

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Draft in process


Contact Information

Allison Scott, Ph.D.Applications EngineerAzbil BioVigilant

+ 1(520)292-2342 x [email protected]

Customer Support+1(520)292-2342

www.biovigilant.com

Jeffrey Weber Allison Scott James Drinkwater · GLP, GMP, GCP, GPvP, GDP Best Practice –risk...

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