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Cleanrooms:Classification versus Monitoring;
Regulations
2
Agenda
• ISO 14644-1: Revisions
• EU GMP ANNEX 1
• What affects Particle Concentration in a cleanroom
• What can be readily controlled to affect concentration
• What are the current trends and dialog that will likely change historic mainstays of cleanroom design
• Setting ALERT and ACTION levels for best effect
• Continuous monitoring for particle counts
3
Measuring Particles: 2 intentions
Classification Monitoring
4
Differences
Classification Monitoring
Frequency6 months or annual;
a formal studyDaily, weekly, monthly
or continuous
Number of positions By formula By need for data
Sample volume By formula By need for data
Pass/Fail criteriaBy table;
one “class limit” value
By need for trend info or control; often
ALERT and ACTION
Reporting format By standard In form needed for rapid understanding
Distribution of counts in a room or zone
Uniform or homogeneous
Unique at each sample position
5
Differences
Classification Monitoring
Focus of assessment Room or Zone Each sample position
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Measuring Particles: 2 intentions
Classification
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– before 1999
Classification Standards for Airborne Particles
General Cleanroom Airborne Particle Monitoring Standards
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Classification Standards for Airborne Particles
– ISO 14644-1• Classification of air cleanliness
– ISO 14644-2• Specifications for testing and
monitoring to prove continued compliance with ISO 14644-1
– ISO 14644-3• Guidance on instrumentation to
be used for testing for compliance with ISO 14644-1
General Cleanroom Airborne Particle Monitoring Standards
ISO 14644
1999
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Classification Standard: ISO 14644-1 General Standard for all Industries
Electronics• Semiconductor• Flat Panel• Circuit Board• Optical• MEMS/Nanomachines
Life Sciences• Pharmaceutical• Biotechnology• Medical Devices• Hospitals/Pharmacies
Aerospace• Launch Vehicles• Satellites• Commercial/Military Aircraft
Laboratories• Analytical Laboratories• Universities
Other• Nuclear• Photographic, X-ray films• Automobile Painting
Electronics
Life Sciences
Aerospace
LaboratoryOther
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Classification Standard: ISO 14644-1:1999
Purpose
• Defines cleanroom classes
• Establishes minimum sampling volume – Purpose: Gather a sample volume with theoretically
at least 20 particles for a statistically valid sample
• Establishes minimum number of points to classify area, based on statistical criteria– Gather a representative sample of the total air volume from a
statistically valid number of locations
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Class Number of Particles per Cubic Meter by Micrometer Size
0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1,000 237 102 35 8
ISO 4 10,000 2,370 1,020 352 83
ISO 5 100,000 23,700 10,200 3,520 832 29
ISO 6 1,000,000 237,000 102,000 35,200 8,320 293
ISO 7 352,000 83,200 2,930
ISO 8 3,520,000 832,000 29,300
ISO 9 35,200,000 8,320,000 293,000
FS 209E Class 100
FS 209E Class 10,000
FS 209E Class 100,000
Table for ISO Classes;Classification Limits: ISO 14644-1:1999
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Revised Table for ISO Classes;Classification Limits: ISO 14644-1:2015
ISO 0.1 µm 0.2 µm 0.3 µm
Number of Particles per Cubic Meter by Micrometer Size
0.5 µm 1 µm 5 µm
1 10
237 102 35
2 100 24 10
4 10,000 2,370 1,020 352 83
3 1,000
8,320 293
5 100,000 23,700 10,200 3,520 832
352,000 83,200
6 1,000,000 237,000 102,000 35,200
2,930
8 3,520,000 832,000 29,300
7
293,0009 35,200,000 8,320,000
Revisions to ISO 14644-1
( Effective December 2015 )
Major change #1:
Minimum number of sample locations
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Revisions to ISO 14644-1
Method of determining minimum number of sample positions
– Previously determined by taking the Square Root (SQRT) of measurement area (in square meters)
– Replaced with stated number of minimum sample positions as a look-up chart
– Will mean a modest increase in the number of sample points in almost all cases
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Area of cleanroom (m2) less than or equal to
Minimum number of sample locations to be tested (NL)
2 1
4 2
6 3
8 4
10 5
24 628 732 836 952 1056 1164 1268 1372 1476 15104 16108 17116 18148 19156 20192 21232 22276 23352 24436 25636 26
1000 27 > 1000 See Equation A.1
Table A.1 — Sample locations related to cleanroom area
A.4.1 Establishment of sampling locations
Derive the minimum number of sampling locations, NL,
from Table A.1.
Table A.1 provides the number of sample locations related to the area of each
cleanroom or clean zone to be classified and provides at
least 95 % confidence that at least 90 % of all locations
do not exceed the class limits.
Major change #2:
Specific Calibration Method
( ISO 21501-4 )
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ISO 21501-4: Additional Tests
Basic calibration• Size calibration• False count rate• Sampling Flow Rate• Sampling Time
ISO 21501-4 • Size calibration• False count rate• Sampling flow rate• Sampling time• Verification of size setting• Counting efficiency• Size resolution• Concentration limit• Sampling volume
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Repeatability
Measurement #1
Measurement #2
Measurement #3
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Repeatability
6 months 12 months
21
Reproducibility
Impact on
- EU GMP Annex 1
- PIC/s EU GMP Annex 1
- DR Norm 32
None directly !!!
But …
because these reference ISO 14644-1 to determine the minimum number of sample points, there is an effect . . .
24
Area of cleanroom (m2) less than or equal to
Minimum number of sample locations to be tested (NL)
2 1
4 2
6 3
8 4
10 5
24 628 732 836 952 1056 1164 1268 1372 1476 15104 16108 17116 18148 19156 20192 21232 22276 23352 24436 25636 26
1000 27 > 1000 See Equation A.1
Table A.1 — Sample locations related to cleanroom area
A.4.1 Establishment of sampling locations
Derive the minimum number of sampling locations, NL,
from Table A.1.
Table A.1 provides the number of sample locations related to the area of each
cleanroom or clean zone to be classified and provides at
least 95 % confidence that at least 90 % of all locations
do not exceed the class limits.
25
1. New ISO revisions took effect in late 20152. For most areas, additional sampling points will be
required3. Cost:
– More time to sample at additional points– More data to record– More data to analyze
4. Benefit:– Better quality of data, leading to higher confidence the room will
perform as needed
New instrument designs can help mitigate impact.
Summary
26
Intuitive User Interface!
• Wizard to conduct pass/fail test for:– ISO 14644-1– EU-GMP Annex I – FS 209E standards
• No expertise in standards required. Just a few clicks to compliance
• The wizard guides an operator step by step to sample data, process data and product reports
Test wizard for standards compliance
MET ONE Simply Paperless:Files exported to Excel straight from the
counter via Ethernet, WiFi or USB –eliminates manual data transcription
Manual methods mean…
• lost printouts• rework
• wasted time• data entry errors
2 No more manual data entry!
Built in workflow tools3
MET ONE Simply Paperless:Step-by-step directions for EM program. Comments/alarm reasons added via the
counter touch-screen.
1. Take particle count
sample
2. Click ‘Export’
3. Data transferred automatically via your network in .pdf, .csv and .xml formats
Options:a) Retain .pdf, .csv and .xml
ora) Feed data direct into LIMS
Accurate, 21CFR part 11 compliant data transfer!
MET ONE Simply Paperless increases EM productivity while improving compliance by
eliminating data errors/data gaps.
Easy integration into LIMS5
Fully electronic records
Option of full LIMS integration
1
MET ONE Simply PaperlessSummary
Built-in workflow tools
No more manual data entry
No more scanning printouts
2
Step-by-step directions, eliminating data gaps. Includes location labels, sample recipes, sample review/commen
3
54
Eliminate paper print-outs and scanning/photocopying
Eliminate manual data transcriptions
+20% productivity increase
Save up to 1½ hours per day
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Measuring Particles: 2 intentions
Classification:ISO 14644-1; Annex 1
Monitoring:Your SOP
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Two types of Monitoring !!!
• Daily, weekly, monthly, quarterly
• General 1 to 3 samples each time
• Static or dynamic• General need is to
show consistency over time – trend
• CAUTION:Conditions and sources must be identical to draw any conclusions
“EM” Intermittent• Continuous during
process/setup• Frequent consecutive
samples, often at 1-minute intervals
• Watching for heightened risk due to contamination
• “Normal” operations can cause brief spikes in counts
Process Control
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Key Points about Cleanrooms
Cleanrooms are dynamic; particle concentrations change with location and with time
Particle counts can fluctuate considerably but yet be normal
Studying the actual particle count values over a long period of time is often critical to setting good values for ALERT and ACTION levels
Strategies for setting ALERT and ACTION levels will likely be different for continuous PROCESS control versus intermittent EM sampling
35
What affects Particle Concentration in a cleanroom ???
Why do we care about Particle Counts?Pharmaceutical, Biotechnology
– Particles in injection could cause occlusion of blood vessels
• Red Blood cells are about 6 to 8 µm• Capillary (5 to 10 µm) • Arterioles and venules (10 to 50 µm)
– Viables in injection can trigger infection– Possibility of reaction to foreign substances
(RES/allergic reaction)
Medical DevicesPoor adhesion of medicated coating in
stent creates embolisms
Increased risk of infection or rejection of orthopedic implants
What price patient safety?
Injections and infusions for people with suppressed immunological systems
Injection straight into bloodstream bypasses most of the body’s defences.
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Cleanrooms and Clean Zones
“Cleanrooms and associated controlled environments
provide for the control of contamination of air or surfaces to
levels appropriate for accomplishing contamination
sensitive activities. Contamination control can be beneficial
for protection of product or process integrity in applications
such as the aerospace, microelectronics, pharmaceuticals,
medical devices, healthcare, food, etc.”
ISO 14644-1
39
Cleanrooms and Clean Zones
3.1.1 cleanroom
Room within which the number concentration of airborne
particles is controlled and classified, and which is designed,
constructed and operated in a manner to control the
introduction, generation, and retention of particles inside the
room.
ISO 14644-1
What can go wrong?
A cleanroom or cleanzone usually starts out clean• What are my potential sources of contamination?
– How can I eliminate, minimize or control them?
• How does my room or zone remove particles?– In what direction(s)?
– How fast?
– How many occupants can be in there at one time?
• Is my cleaning service effective?• How can I test or monitor to know I’m OK?
The equation
Particlegeneration
Rate -----------------
Expected Counts per
volumeDilution
rate
Removal efficiencyx =
42
Particle Generation: Sources
Filtered AirLeakage into RoomMachineryPeopleDeposition > re-circulation
What can go wrong?
Do you know which way the wind blows?
Particle events !!
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Key Take-away #1
Particle concentration varies by:
A) Location
B) Time
The equation
Particlegeneration
Rate -----------------
Expected Counts per
volumeDilution
rate
Removal efficiencyx =
52
53
Effect of Unidirectional Air Control
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FDA on smoke studies of interventions
Company X
Company X
Company X
57
Smoke tests
People contribute particles
What
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People contribute particles
Study into Human Particle Shedding, Cleanroom Technology, August 2011, pages 26- 28
General Air Monitoring
• Non-viable counts– Sometimes referred to as “total count”– Includes all types of airborne material
• Solid particles• Fibers• Microorganisms• Skin flakes• Droplets
Table salt
Skin flake
Bacteria40 µm
65
What can be readily controlled ???
66
What can be controlled
• Fan Speed/Air Change Rate• Number of sources and source strength• Coverage of Garments• Quality of garments/frequency of
washing/lifetime• Activity of personnel• Workflow and Position in room
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69
Study of people as sources in ISO 5
Contamination of cleanrooms by people, John Sharp et al,European Journal of Parenteral & Pharmaceutical Sciences 2010; 15(3): 5-11
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Study of people as sources in ISO 5
Contamination of cleanrooms by people, John Sharp et al,European Journal of Parenteral & Pharmaceutical Sciences 2010; 15(3): 5-11
71
What are the current trends and dialog that will likely change historic mainstays of
cleanroom design ???
72
Current trends and topics
• Impact of Isolators and RABS• Robots• Energy Conservation• Historic guidelines for Flow Rates and Air change Rates
73
Why reduce air flow/air change rates ?
• Lower air change rates result in smaller fans, which reduce both initial investment and construction cost.
• Fan power is proportional to the cube of air change rates or airflow. A 30-percent reduction in air change rate results in a power reduction of approximately 66 percent.
• By minimizing turbulence, lower airflow may improve cleanliness.
75
Energy conservation – idle times
• If no sources are generating particles (machinery or people), why not turn down the fan speed to save energy?
• Still maintain room characteristics of temperature and humidity as needed
• Need to understand time needed to bring room back to desired levels for active use
What can go wrong?
A cleanroom or cleanzone usually starts out clean• What are my potential sources of contamination?
– How can I eliminate, minimize or control them?
• How does my room or zone remove particles?– In what direction(s)?
– How fast?
– How many occupants can be in there at one time?
• Is my cleaning service effective?• How can I test or monitor to know I’m OK?
77
Summary
Cleanrooms are dynamic; particle concentrations change with location and with time
Particle counts can fluctuate considerably but yet be normal
Studying the actual particle count values over a long period of time is often critical to setting good values for ALERT and ACTION levels
Strategies for setting ALERT and ACTION levels will likely be different for continuous PROCESS control versus intermittent EM sampling
78
Thank you !
+1 541 295 7538
Grants Pass, Oregon USA
Presented by
Joe Gecsey
Life ScienceApplications
