asm thursday 11 july environmental monitoring of production areas … · 2013. 7. 16. · iso...
TRANSCRIPT
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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
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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
Formal Investigation Techniques
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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
Formal Investigation Techniques
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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
Formal Investigation Techniques
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Production error, or lab error
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PW, WFI score high
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1st example
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Production error, or lab error
Formal Investigation Techniques
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Production error, or lab error
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Formal Investigation Techniques
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Production error, or lab error
Formal Investigation Techniques Production error, or lab error
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Formal Investigation Techniques
Production error, or lab error
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Formal Investigation Techniques Production error, or lab error
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Formal Investigation Techniques
Production error, or lab error
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Formal Investigation Techniques
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Summary
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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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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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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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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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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
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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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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
Technical Committee 209 , & International Confederation of ContaminationControl Societies (ICCCS)
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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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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
Control Societies (ICCCS)41
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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.
Technical Committee 209 , & International Confederation of ContaminationControl Societies (ICCCS)
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Surface cleanliness by particles - SCP
Technical Committee 209 , & International Confederation of ContaminationControl Societies (ICCCS)(C) David Buckley July 2013 43
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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
Technical Committee 209 , & International Confederation of ContaminationControl Societies (ICCCS)
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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
Control Societies (ICCCS)45
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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
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