ASM Thursday 11 July Environmental Monitoring of Production Areas … · 2013. 7. 16. · ISO...

12/07/2013

(C) David Buckley July 2013 1

Navigate GMP with DBA

Monday 8 th July 2013

Symposium 1 - Environmental Monitoring of

Production Areas

Dealing with Environmental Monitoring Out of

Specification Results and Changes to ISO 14644

David Buckley

Rev 2 1

Formal Investigation Techniques

(C) David Buckley July 2013

Kaoru Ishikawa

• 1940’s; known for “Democratizing Statistics”

• The Basic Seven Tools made statistical analysis less complicated for the average person

• Good Visual Aids make statistical and quality control more comprehendible.

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What are the Basic Seven Tools of Quality?

• Fishbone Diagrams (Kaoru Ishikawa)

• Histograms

• Pareto Analysis

• Flowcharts

• Scatter Plots

• Run Charts

• Control Charts



Non-conformities fall into three main areas

• System Related

• Product Related

• Process Related

• People are the greatest source of biocontamination

– Unpredictability and uncertainty of Human behaviour

– “80% of the species found in the human upper respiratory

tract cannot be recovered” (IMHO move to RABS is

inevitable)

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Easy



Qualification

choiceAncillary material

location

Sample

Maintenance

Tare weight

Uncertainty

Light

stabilityHumidity

Solutions

Time

Temperature

Correct one used

ValidatedTrained

Proficient

Supervised

competent

Calibration

Dip stick documented

Capable

Environment MachinesMaterials

Measurement People Methods

Laboratory or

production error??

6M – Man, Mother Nature, Materials, Machines, Measurement, Methods

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Positive Sterility Test

Isolator has no overpressure

Environment not sterile

productcontact parts not sterile

Vials not sterile

productfilter not sterile waterfilter

defect

HEPA-Filter defect

Contamination with Water during

filter test

Ventfilter for nitrogen defect

gloves not sterile

Bulksolution not sterile

primary packaging material not sterile

waterfilter not sterile

productfilter defect

gloves defect

Media Filling line with Isolator and Tunnel Handling

Filter Materials Personnel

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Comparison Matrix

Cause

Cause

Man Method Method Environment Measure-ment

Materials

Man

Method

Method

Environment

Measure-ment

Materials

Putting it together � Compare all “causes” 2 at a time� 2 points in the column of more important cause or 1 each if equal� Sum of column gives relative importance or a weighting factor

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Used Ishikawa and looked at 6M

Man Floor – scores low

Machine

Method

Material

Environment

Measurement



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Production error, or lab error

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PW, WFI score high



1st example

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Formal Investigation Techniques Production error, or lab error


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Summary

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© David Buckley

ISO14644, 1 and 2 TC209 mission

• Gordon J Farquharson, is convenor ISO TC209 WG1 • Apply good science and statistics• Remove confusion and inconsistencies• Simplify terms, Use more precision• Use a Table for Classification instead of the universal

formula• Decided to remove classification and keep to Periodic

Testing & Monitoring• Agreed that Classification and Periodic Testing are

NOT the same – amount of testing• Differences over inclusion of Differential Pressure

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© David Buckley

Proposed changes

• Simplify classification process

– If possible remove need to evaluate 95% UCL for 2-9 sample locations

• Review cleanroom classification procedure

– make it more applicable to rooms in operation -contamination isn't expected to be evenly distributed –current assumption

• Generally update the standard to current thinking and industry requirements

• Avoid radical change to current ISO cleanliness classes 1-9 29



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Air flow onto a flat surface (left) and a perforated surface (right)


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What’s new


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© David Buckley

ISO 14644-2:2000 - changes

• Simplifies and clarifies requirements and guidance tables that specify frequency of testing and monitoring of cleanrooms used to demonstrate continued compliance with the cleanliness classification.

• Refined how intervals may be extended, provided that automated monitoring systems show the cleanroom is under control.

• Provide new guidance on aspects that should be considered when configuring a monitoring system for a cleanroom.

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© David Buckley

ISO 14698 not in line with ISO 14644

• No Tables of Classification

• Not up to date with Risk Assessment & Risk Management techniques (eg ICH Q9 QRM)

• No Check Lists of “Things to Consider”

• Not up to date with technology advances in Rapid Microbiological Methods (RMM) & Instantaneous Microbiological Detection (IMD) (eg ATP, Bioluminescence)

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© David Buckley

PIC/S EU GMP Overules ISO14644

• In Grade A and B zones, the monitoring of the ≥5.0 µm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure.”• “... consecutive or regular counting of low

levels (of ≥5.0 µm) is an indicator of a possible contamination event and should be investigated.”

• Particles ≥5.0 µm could be skin particles carrying biocontamination

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ISO Class, old and new ISO 14644 - 1999


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Sample locations

The formula proposed for intermediate decimal classes in ISO DIS 14644-1:2010



© David Buckley

Developments since 2010

Revisions• 14644-1 DIS in 2010 because of change in TC209 vision and

comments new DIS is under development.• 14644-2 is developed parallel to 14644-1 and will be on

monitoring only.• 14644-6 Vocabulary will be removed and becomes web based• 14644-10 DIS in 2011 Surface Cleanliness by Chemical

concentrations• • 14644-x will be the Assessment of equipment and materials for

cleanroom suitability.• • 14644-12 is reserved for Air Cleanliness by Nanoscale Particle

concentration. Classification is extrapolation of 14644-1 to 1 nm.• • 14644-13 is reserved for Cleaning of surfaces to achieve

defined levels of cleanliness in terms of particle and chemical classification.

Technical Committee 209 , & International Confederation of ContaminationControl Societies (ICCCS)

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© David Buckley

ISO 14644-3 Test methods

• Particle measurement is moved to 14644-1,– Ultrafine particles are moved to nanoscale particles.– Supporting tests for the cleanroom performance:

• Air pressure difference test• Airflow test• Airflow direction test and visualisation• Recovery test• Temperature, humidity and micro vibration tests.

• Supporting tests for the performance of systems and components, which maintain cleanrooms:– Installed filter leakage test– Containment leak test– Electrostatic and ion generator tests– Particle deposition test


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© David Buckley

ISO 14644-3 Test methods

• Important changes in test methods:– New knowledge in cleanroom technology and

contamination control and developments in cleanroom components like Fan Filter Units (FFU’s) and measurement equipment are included.

– Installed filter testing by photometer will be improved to prevent unnecessary contamination.

– Installed filter testing by particle counter will be simplified and improved.

– Recovery test will be improved.– Particle deposition measurement is extended to

particle size distributions.Technical Committee 209 , & International Confederation of Contamination

Control Societies (ICCCS)40

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© David Buckley

14698-9 viables 3 sections:

1. Establish control requirements:• Product quality attributes,• Risk assessment,• A distinction between harmless and harmful microorganisms

will be made.• Classification of Air and Surface Cleanliness by viables:• < 10-10.000 cfu/m3 -> ACVx 1-4• < 4-300, > 300 cfu/m2 +sample area: 1dm2 or m2 -> SCVx 1-5

2. Test methods (air, surface and deposition):• New rapid methods will be included.3. Demonstrate control.Technical Committee 209 , & International Confederation of Contamination



© David Buckley

Surface cleanliness by particle concentrations 14644-9 (2012) ISO SCP class

• The surface cleanliness by particles is classified by the number of particles ≥ 1 µm per m2.

• The SCP class is the 10log(N1) , where N1 is the maximum number of particles ≥ 1 µm per m2,

• The SCP class can be written as 10log(d.Nd ) , where Nd is the maximum number of particles ≥ d µm per m2 and d is the size (length) of the particle. CN= 10K /d, where CN is Nd per m2 and K = SCP class.

• Direct and indirect measurement methods are described in the standard.


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Surface cleanliness by particles - SCP

Technical Committee 209 , & International Confederation of ContaminationControl Societies (ICCCS)(C) David Buckley July 2013 43


© David Buckley

SCP measurement

• Direct– Particle surface monitor, Particle Guard, (Stereo)

microscope, – Black light (qualitative, vision)– Plus others

• Indirect through medium– Air, Air flow + particle counter, Liquid– Filtrate + weighting or microscopic inspection– Liquid particle counter – Solid (wiper, tape, sticky

roll) + microscopic inspection


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© David Buckley

Future developments

• 4 contaminants :– Particles (0,1 – 5 µm and macro descriptor),– Nanoscale particles (1 – 100 nm),– Chemicals,– Viables (micro-organisms).

• Classification of Air cleanliness for one of the 4 contaminants.

• Classification of Surface cleanliness for one of the 4 contaminants.

• Measurement method for classification in standard.

• Revision of 14644-3 test methods.Technical Committee 209 , & International Confederation of Contamination



© David Buckley

ISO14644 Conclusion

• TGA voice????? ISO Standards are NOT industry specific, PIC/S still applies

• Cannot “Monitor a process into Control”

• Not enough clarity on differences, issues and guidance on Aseptic vs Non Sterile applications

• Not enough guidance on Airborne vs Surface biocontamination risks and control

• Overall seen as not easy to read & use

• Let “good science” prevail46

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Questions


ASM Thursday 11 July Environmental Monitoring of Production Areas … · 2013. 7. 16. · ISO...

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