Post on 09-Oct-2020
Cleanrooms:Classification versus Monitoring;
Considerations of Removal EfficiencySetting Alerts and Actions
2
Agenda
• Classification versus Monitoring
• 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
3
Conclusion
Two key thoughts:
1. Know and control sources of contamination
2. Understand how the area/room removes contamination
4
Sources of contamination
Sources:In-filtrationFiltered airMachinesProcessesMaterialsPeople
- How many- Gowning level and execution
5
Removal Efficiency
• Quantity of filtered air• Quality of filtered air• Turbulence• Impact of convection• Cleaning routines
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Measuring Particles: 2 intentions
Classification Monitoring
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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
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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
Classification Standard: ISO 14644-1:1999Limits
FS 209E Class 10,000
FS 209E Class 100,000
21
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
( December 2015 )
Major change #1:
Minimum number of sample locations
24
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 21501-4:1997 )
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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
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Reproducibility
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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.
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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
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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!
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Built in workflow tools3
MET ONE Simply Paperless:Step-by-step directions for EM program. Comments/alarm reasons added via the
counter touch-screen.
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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
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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
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 . . .
40
Classification– Sections 4 through 7
Monitoring – Sections 8 through 17
EU Annex 1:Latest revision (2009)
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EU Annex 1 Summary:Classification
Classification – Sections 4 through 7
Section 4:“Classification should be clearly differentiated from
operational process environmental monitoring.”
Section 5:“ For classification purposes in Grade A zones, a minimum
sample volume of 1 m3 should be taken per sample position.
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EU Grade Definitions
• Zone grades according to risk of product contamination• Particle count measurements at 0.5 µm and 5 µm• “At rest” vs “In operation”
Grade Activity 0.5 µm 5 µm 0.5 µmA High Risk - filling, open vials, stopper bowls 3 520 20 3 520 20B Aseptic preparations 3 520 29 352 000 2 000C Clean area of less critical operations 352 000 2 000 3 520 000 20 000D Clean area of less critical operations 3 520 000 20 000 not defined not defined
at rest in operationmaximum permitted number of particles/m3 equal to or above
5 µm
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Grade
0.5 µm 5 µm 0.5 µm 5 µm
A 3 500 1 3 500 1
B 3 500 1 350 000 2 000
C 350 000 2 000 3 500 000 20 000
D 3 5000 000 20 000 not defined not defined
At Rest In Operation
Maximum permitted number of particles/m3
equal to or greater than the tabulated sizeGrade
0.5 µm 5 µm 0.5 µm 5 µm
A 3 520 20 3 520 20
B 3 520 29 352 000 2 900
C 352 000 2 900 3 520 000 29 000
D 3 520 000 29 000 not defined not defined
At Rest In Operation
Maximum permitted number of particles/m3
equal to or greater than the tabulated size
Limits at 5 microns for Grade A1 per cubic meter 20 per cubic meter
EU Annex 1:Latest revision (2009)
44
EU Annex 1 Summary:Classification
Section 5:
“For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the [minimum] sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.”
45
EU Annex 1 Summary:Classification
Section 5 (continued)“For classification purposes EN/ISO 14644-1 methodology
defines both the minimum number of sample locations and the [minimum] sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.”
Number of locations
• Based on lookup table
Sample Volume (B,C,D)
46
EU Annex 1 Summary: Monitoring
Monitoring: Sections 8 through 17Section 8:“Clean rooms and clean air devices should be routinely
monitored in operation and the monitoring locations based on– a formal risk analysis study and – the results obtained during the classification of rooms and/or
clean devices”
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Section 9• “The Grade A zone should be monitored at such a
frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded.
= “continuous” !!!
EU Annex 1 Summary: Monitoring
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Section 12:• “The sample sizes taken for monitoring purposes using
automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.”
• It is not necessary to sample 1m3 during verification or monitoring
• Particle counters used for monitoring may have the same or different flow rate from those used for classification.
EU Annex 1 Summary: Monitoring
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Monitoring Positions: Risk-based Approach
Lyo 1
Lyo 2
Lyo 3
VialSterilizing
Tunnel
3
4
5
6
7
1
2
• Monitoring must follow the workflow, covering areas where product is exposed – Annex 1 (2009)− Where open vials exit de-pyrogenation – human interaction (1)− Where vials are filled (2,3)− Surrounding Grade B background (4)─ Where the vials are partially stoppered (5)─ Loading area in front of lyophilizers must be Grade A if
product is not fully stoppered (6,7)
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In a filling operation for which the final product remains liquid, some points established for a lyophilized product would not be needed.
2 3
4
Vial Washing System
1
Monitoring Positions: Risk-based Approach
51
Measuring Particles: 2 intentions
Classification:ISO 14644-1; Annex 1
Monitoring:Your SOP
52
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
53
What affects Particle Concentration in a cleanroom ???
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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
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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 =
58
Particle Generation: Sources
Filtered AirLeakage into RoomMachineryPeopleDeposition > re-circulation
What can go wrong?
Do you know which way the wind blows?
Particle events !!
62
Key Take-away #1
Particle concentration varies by:
A) Location
B) Time
63
64
Effect of Unidirectional Air Control
65
FDA on smoke studies of interventions
Company X
Company X
Company X
66
FDA’s Inspectional Observations (483’s) on Air Flow Pattern Visualization
1. Smoke studies in ISO 5 hoods were not conducted under dynamic conditions.
2. There has been no air flow pattern (i.e smoke study) evaluation study performed to determine the acceptability of the horizontal air flow, that is, the air flow is not compromised (i.e air turbulence/air eddies) during the aseptic operations that are performed in the ISO-5 area.
3. There has been no air flow pattern evaluation to determine that the personnel activities and manual transfer of materials between the ISO-8 and ISO-7 areas negatively affect the air movement and air cascade.
4. Smoke studies have not been properly documented for the air flow patterns of the ISO 6 class rooms or ISO 5 laminar air flow hoods used in the processing of injectable products.
67
FDA’s Inspectional Observations (483’s) on Air Flow Pattern Visualization
5. The air flow pattern video does not present data to adequately assess the requested “downward sweeping air flow pattern” for the ISO 5 aseptic fill zone. The firm failed to evaluate the potential product impact of the turbulence, air eddies observed in the middle of the ISO 5 hoods during dynamic operations.
6. Smoke study did not include an evaluation of the personnel activities performed in the adjacent ISO 5 hoods to determine that the personnel activities do not negatively affect air flow patterns within ISO 5 hoods.
7. The smoke study does not demonstrate critical aseptic connections performed during the assembly of filling equipment used to fill sterile pharmaceuticals within ISO 5 hoods
68
Smoke tests
Airflow Visualization Techniques and Practices - August
Aug 15 - Aug 17, 2017 / Bethesda, MD
People contribute particles
What
74
People contribute particles
Study into Human Particle Shedding, Cleanroom Technology, August 2011, pages 26- 28
The equation
Particlegeneration
Rate -----------------
Expected Counts per
volumeDilution
rate
Removal efficiencyx =
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
80
What can be readily controlled ???
81
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
82
84
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
85
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
86
What are the current trends and dialog that will likely change historic mainstays of
cleanroom design ???
87
Current trends and topics
• Impact of Isolators and RABS• Robots• Energy Conservation• Historic guidelines for Flow Rates and Air change Rates
88
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.
90
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
91
Cleanroom???
92
• Control of people emissions – good garments are the primary control measure
• Positive pressure to ensure external contamination is excluded • well-sealed and cleanable cleanroom envelope to minimise
uncontrolled leak paths • Correctly positioned, integral terminal H14 HEPA filters and housings to
supply particle free (no particles ≥0.5µm) air to the room• Good ventilation effectiveness to ensure clean supply air is providing
good dilution and removal of contamination• Cleanroom supply diffusers to effectively distribute clean air into the
room • Low level extraction to help flushing away contamination • A HVAC system to supply and extract sufficient contamination free
airflow to dilute and remove residual contamination from the room
Cleanroom airborne contamination control
93
It depends who you ask……Some companies (customers & designers) still talk about airflow in terms of needing a certain minimum number of air-changes per hour (ac/hr) to meet their cleanliness requirements….
What does “sufficient airflow” mean?
94
Typical ac/hr across industry
95
• Unpredictable cleanliness levels• Cleanrooms which are much cleaner than they are required to be• Possibly less clean operationally than required • Facilities which are much larger than necessary (AHU / Ducts etc)• Facilities which are more costly to build than necessary• High HVAC energy use• Greater emissions• Greater impact on the environment• Less sustainable• Sub-optimised
Air-change rate as a basis for design leads to..
96
Follow the science, consider HVAC design based on a Scientific approach rather than ad-hoc air-changes to ensure an optimised and transparent solution is delivered.
What’s the answer?
97
A scientific approach to determine airflow
Determine emissions into the room (D), agree required level of cleanliness in the room (C), and calculate the amount of supply air required (considering
ventilation effectiveness)
100
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Removal or Ventilation Efficiency
Monitoring Compressed Air/Gasfor Particles
10
103
FDA: Air (CDA) or Gas that contacts Product
104
Frequency of sampling and target levels for CDA/Gases
It would seem that the authorities have not established a periodicity for sampling of compressed gas sources. In cases where there is concern that there might be some risk, it may be wise to sample gas sources on a quarterly basis and to set an expectation of an ISO 7 level in non-sterile applications; for sterile areas, a target of ISO 5 or better should be used. Many customers look for an ISO 4 level in sterile gas supplies and this should be achievable with most commercially available filter methods. This higher target level is, however, one of choice, rather than one dictated by regulation (but does add some safety margin).
Also, for sterile areas, a more frequent - monthly or even weekly -sampling may help minimize any lengthy period of heightened risk due to a system failure.
Air (CDA) or Gas that contacts Product
105
MET ONE 3400 for CDA/Gas testing
Ordering a Particle Counter for Gas SamplingThe new 3400 gas option, together with the appropriate High Pressure Diffuser (HPD), makes gas monitoring straight-forward. The user simply selects the required gas from a pull-down list on the 3400 interface; the sample flow is automatically adjusted to ensure that a calibrated flow rate is maintained to specification.
Ordering a new 1 CFM 3400 with gas calibration is likewise straight-forward. Four versions are available, and include gas calibrations for these gases: Air, N2, and CO2.
2088900-06 3413 0.3 micron, 1 CFM, GASES2088900-07 3413 0.3 micron, 1 CFM, GASES, WIFI2088900-08 3415 0.5 micron, 1 CFM, GASES2088900-09 3415 0.5 micron, 1 CFM, GASES, WIFI For the 1 CFM counters listed above, select the 2080732-13 HPD. Note that HPD
versions are available for other flow rates when CDA and/or N2 are the only gases to be sampled.
106
MET ONE Diffusers for CDA/Gas
107
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
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?
109
Conclusion
Two key thoughts:
1. Know and control sources of contamination
2. Understand how the area/room removes contamination
110
Thank you !
joegecsey@gmail.com
+1 541 295 7538
Grants Pass, Oregon USA
Presented by
Joe Gecsey
Life ScienceApplications