regulations concerning airborne particle counting
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Regulations Concerning Airborne Particle CountingAirborne Particle Counting
Particle Counting ApplicationsApplications
Two types of activities performed with an airborne particle counter:
Environment
Classification focuses primarily on the environment
Environment
Monitoring focuses on process, people and the environment
PeopleProcess
People as a Contamination SourceShed 5 to 10 million skin cells each dayShed 5 to 10 million skin cells each day
2000 to 5000 microorganisms/cm2 on skinFilter efficiency of clothing or garment varies greatly
2
Classification:FS209 and ISO 14644-1
FED STD 209EISO 14644-1
FS209 and ISO 14644-1
Classification is the process of qualifying the English Metric
1
ISO Class
2
cleanroom environment by the number of particles using a standard method
D i l ifi i f di1 M1.5
10 M2.5
3
4
Determine classification of room according to standards
“ISO Class 5” or “Class 100”
Performed on a regular basis but not frequently
100 M3.5
1,000 M4.5
5
6
6 months, yearly or ???
Standards define minimum number of sample pointsUsually based on area of cleanroom or clean zone
10,000 M5.5
100,000 M6.5
7
8
Standards define minimum amount of air to be sampled
Minimum volumes for statistically valid samples
3
9 Classification is a standardized method
Environmental Monitoring
Determine stability of room or zone over time; develop trend data
Executed on a scheduled basis: daily weekly monthly
Minimum number of sample points defined by QA
Executed on a scheduled basis: daily, weekly, monthly
– Area of cleanroom or clean zone– Activity– Risk to product
Frequency and volume of sample points defined by QA– Frequent enough to show control– Frequent enough to provide
meaningful trend information
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Not controlled by regulation…but need for trend information
Process MonitoringDetermine readiness of room to carry out designated task
Performed whenever relevant activity occurs – daily work
Minimum number of sample points defined by QAA f l l
Performed whenever relevant activity occurs daily work
Area of cleanroom or clean zoneActivityRisk to product
Frequency and volume of sample points defined by QAF t h t h t lFrequent enough to show controlFrequent enough to manage
financial risk of product contamination N d i d b l i b b i k!
5
contamination Not determined by regulation…but by risk!
Differences
Classification MonitoringFrequency 6 months or annual Daily, weekly, monthly
or continuous
Number of positions By formula By need for dataNumber of positions By formula By need for data
Sample volume By formula By need for data
Pass/Fail criteria By table By need for trend info or controlor control
Reporting format By standard In form needed for rapid understanding
6
Differences
Classification Monitoring
Distribution of counts in a room or zone
Uniform or homogenous
Unique at each sample position
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Classification
8
Classification Standards for Airborne Particles
General Air Monitoring Standards – before 1999
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Classification Standards for Airborne Particles
General Air Monitoring Standards
– ISO 14644-1• Classification of air cleanliness
– ISO 14644-2• Specifications for testing and
monitoring to prove continued compliance with ISO 14644-1
– ISO 14644-3ISO 14644 3• Guidance on instrumentation to
be used for testing for compliance with ISO 14644-11999
ISO 14644
10
G l St d d
Electronics
General Standard for all Industries
Electronics• Semiconductor• Flat Panel• Circuit Board• Optical• MEMS/Nanomachines
Life Sciences• Pharmaceutical• Biotechnology• Medical Devices• Hospitals/Pharmacies
ElectronicsLaboratoryOther
Aerospace• Launch Vehicles• Satellites• Commercial/Military Aircraft
Laboratories Life Sciences
Aerospace
• Analytical Laboratories• Universities
Other• Nuclear• Photographic, X-ray films
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• Automobile Painting
ISO 14644
ISO 14644 consists of the following parts, under the general title Cleanrooms and associated controlled environments:and associated controlled environments:
Part 1: Classification of air cleanliness by particle concentrationPart 2: Monitoring to provide evidence of cleanroom performance by airbornePart 2: Monitoring to provide evidence of cleanroom performance by airborne
particle cleanliness.Part 3: Test methodsPart 4: Design construction and start upPart 4: Design, construction and start-upPart 5: OperationsPart 6: VocabularyPart 7: Separative devices (clean air hoods gloveboxes isolators and miniPart 7: Separative devices (clean air hoods, gloveboxes, isolators, and mini-
environments)Part 8: Classification of airborne molecular contaminationPart 9: Classification of surface cleanliness by particle concentration
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Part 9: Classification of surface cleanliness by particle concentrationPart 10: Classification of surface cleanliness by chemical concentration
Classification Standard: ISO 14644 1 1999ISO 14644-1:1999
• Defines cleanroom classes in a zone• Defines cleanroom classes in a zone
• Establishes minimum sampling volumes p g– 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 from a valid number of locations for a representative
sample of the total air volume
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Classification Standard: ISO 14644 1 1999 Li it
Cl N b f P ti l C bi M t b Mi t Si
ISO 14644-1:1999 Limits
Class Number of Particles per Cubic Meter by Micrometer Size
0.1 m 0.2 m 0.3 m 0.5 m 1 m 5 m
ISO 1 10 2ISO 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
FS 209E Class 100
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
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ISO 9 35,200,000 8,320,000 293,000
Classification Standard: ISO 14644 1 1999ISO 14644-1:1999
2.0 literMinimum sample volume
Minimum sample time 1 minute
Minimum number of locations
1with at least 3 samples
total
Note: Typical sample volume may be larger than minimum listed above especially for smaller size particles in very clean areas (better than ISO Class 5
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or FS 209E Class 100)
Classification Standard: ISO 14644 1 1999
Minimum Sample Volume
ISO 14644-1:1999
Minimum Sample Volume (in liters)
ISO Class 5, 0.5 microns = (20/3520) x 1000 = 5.6 liters
ISO Class 5 5 microns = (20/29) x 1000 = 690 liters
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ISO Class 5, 5 microns = (20/29) x 1000 = 690 liters
ISO 14644-2:2000Continued complianceContinued compliance
(re-qualification)
Schedule of Tests to Demonstrate Continuing Compliance
Test Parameter Class Maximum Time Test Procedure
Particle Count ≤ ISO 5 6 Months ISO 14644-1
Test Parameter Class Interval Test Procedure
Air Pressure All Classes 12 Months ISO 14644-1
Test Annex AISO 6, 7, 8, 9 12 Months
Airflow All Classes 12 Months ISO 14644-1 A B4
Difference All Classes 12 Months Annex B5
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Annex B4
ExampleISO 14644 1 C l l tiISO 14644-1 Calculations
FreezeDryer 1
Vial Washing System 5 m
FreezeDryer 28 m
5 m
FreezeDryer 3
5Calculations for Number of Points:
Area of clean zone = 80 m²
Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions
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4 m
g p g p p
ExampleISO 14644 1 C l l tiISO 14644-1 Calculations
FreezeDryer 1
Vial Washing SystemSystem
1 2 3 4 5 6
7
FreezeDryer 2
Calculations for Number of Points:
Area of clean zone = 80 m²8
FreezeDryer 3
Area of clean zone = 80 m²
Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions9
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ExampleISO 14644 1 C l l ti
1 2 3 4 5 6 7 8 9 10
ISO 14644-1 Calculations
FreezeDryer 1
Vial Washing System
F
System
FreezeDryer 2
• Need to adjust for equipment in room.
• Under ISO 14644-1, if you sample at 10 or more iti id th dd d l l ti f
FreezeDryer 3
positions, you can avoid the added calculation of the UCL (Upper Confidence Limit). Calculation of the UCL is only mandated when the number of positions used is between 2 and 9.
• Best to sample near potential problem spots which
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are near entrances and exits and near operator positions.
ExampleISO 14644 1 C l l tiISO 14644-1 Calculations
FreezeDryer 1
Vial Washing System
1
2
8
9
10
Freeze
2
3 4 5 6 711
12Dryer 2
• Need to adjust for equipment in room.
• Under ISO 14644-1, if you sample at 10 or more positions, you can avoid the added calculation of
12
13
FreezeDryer 3
the UCL (Upper Confidence Limit). Calculation of the UCL is only mandated when the number of positions used is between 2 and 9.
• Best to sample near potential problem spots which are near entrances and exits and near
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operator positions.
ExampleISO 14644 1 C l l tiISO 14644-1 Calculations
1. Average the sample data values at each position1. Average the sample data values at each position2. Normalize the average to “number of particles per cubic meter”3. Compare normalized value to the target class limit; normalized
value at each and every sample point must be less than thevalue at each and every sample point must be less than the limit for the given size and target room classification
If the number of points sampled is more than 1 but less than 10If the number of points sampled is more than 1 but less than 10,then the UCL factor must be applied:
a) Calculate the standard deviationb) Use Student’s T factor from tablesb) Use Student’s T-factor from tablesc) Calculate UCLd) Compare to classification limit; UCL must
not exceed the applicable limit
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not exceed the applicable limit
Probable Revisions to ISO 14644-1, -2
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Revisions to ISO 14644 1:1999ISO 14644-1:1999,
14644-2:2000Revision committee has met
in Zurich in the beginning of September 2012; b WEBEX i J l 2013by WEBEX in July 2013:in Reno October 2013
• Revision process still ongoing• Revision process still ongoing• Likely to be end of 2013 before new draft(s)
submitted for vote vote is recordedsubmitted for vote, vote is recorded,• If draft is accepted, then effective late 2014
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Forthcoming Revisions to ISO 14644 1ISO 14644-1
1. Frequency of re-certification for “continued1. Frequency of re certification for continued compliance”:Now:
• If zone is ≤ ISO Class 5, every 6 months• If zone is ≥ ISO Class 6, every 12 months
Proposed:• Remove re-certification periodRemove re certification period• Re-certification timeframe will be set by regulatory or advisory
committees for a particular industry• Or: 1 year if not monitoring !!
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• Or: 1 year if not monitoring !!
Forthcoming Revisions to ISO 14644 1ISO 14644-1
2. Eliminate calculation of UCL (Student’s T test)
for sample plans with 2 to 9 sample positions
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Forthcoming Revisions to ISO 14644 1
3 Method of determining minimum number of
ISO 14644-1
3. Method of determining minimum number of sample positions
– Replace with stated number of minimum sampleReplace with stated number of minimum sample positions as a look-up chart
– Based on 95% confidence levels not on SQRT of area
– May mean a small increase in the number of sample pointspoints
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A.4.1.1
Derive the minimum number of sampling locations NL from table 3.
Table A.1 shows the number of sample locations related to the
area of each cleanroom or cleanarea of each cleanroom or clean zone to be classified and provides
at least 95% confidence that at l t 90 % f th t t l dleast 90 % of the total area does
not exceed the class limit.
Different levels of confidence andDifferent levels of confidence and verification can be specified and
agreed upon by the customer and li
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supplier.
Forthcoming Revisions to ISO 14644 1
4 Remove possibility to classify at 5 micron
ISO 14644-1
4. Remove possibility to classify at 5 micron only for ISO Class 5
Limit number of 29 removed
Replace number with “Note (e)” :
Sample collection limitations for both particles in low concentrations and sizes greater than 1 um make
classification inappropriate, due to potential particle
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pp p , p plosses in the sampling system.”
Forthcoming Revisions to ISO 14644 1
5 Indicate that single digit limits for
ISO 14644-1
5. Indicate that single digit limits for ISO Class 1 and 2 create challenges to timely executiony
R l b l ith “N t (b)” Replace number values with “Note (b)” :
These concentrations will lead to large air sample These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied; see Annex D.
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Forthcoming Revisions to ISO 14644 1 2
6 New label for classification level
ISO 14644-1, -2
6. New label for classification level
ACP = Air Cleanliness (by) Particles
ACC = Air cleanliness (by) Chemicals
SCP = Surface Cleanliness (by) Particles
SCC = Surface Cleanliness (by) ChemicalsSCC = Surface Cleanliness (by) Chemicals
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Cleanroom Designations
Air Surfaces
Particles ACP SCPISO 14644 – 9ISO 14644 - 1, - 2
Draft #2 of Revision
ChemicalsSCCACC
ISO 14644 10ISO 14644 8 ISO 14644 – 10ISO 14644 – 8
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Classification Limits: ISO 14644-1:1999
Number of Particles per Cubic Meter by Micrometer Sizep y
0.1 m 0.2 m 0.3 m 0.5 m 1 m 5 m
ISO Class 1 10 2
ISO Class 2 100 24 10 4
ISO Class 3 1,000 237 102 35 8
ISO Class 4 10,000 2,370 1,020 352 83
ISO Class 5 100,000 23,700 10,200 3,520 832 29
ISO Class 6 1,000,000 237,000 102,000 35,200 8,320 293
FS 209E Class 100
, , , , , ,
ISO Class 7 352,000 83,200 2,930
ISO Class 8 3,520,000 832,000 29,300
33
ISO Class 9 35,200,000 8,320,000 293,000
Proposed new limits and labels:pClassification Limits: ISO 14644-1 (2014)
ISO-ACP
1 10
0.1 m 0.2 m 0.3 m
Number of Particles per Cubic Meter by Micrometer Size
0.5 m 1 m 5 m
3 1,000 237 102 35
2 100 24 10
1 10
6 1,000,000 237,000 102,000 35,200 8,320 293
5 100,000 23,700 10,200 3,520 832
4 10,000 2,370 1,020 352 83
FS 209E Class 100
293,0009 35,200,000 8,320,000
2,930
8 3,520,000 832,000 29,300
7 352,000 83,200
34
,, , , ,
Forthcoming Revisions to ISO 14644 1 2
7. Calibration of Instruments to ISO 21501-4ISO 14644-1, -2
7.1 Part of Appendix A (Normative):
A 2 2 I lib iA.2.2 Instrument calibrationThe instrument shall have a valid calibration certificate;
the frequency and method of calibration should be q ybased on current accepted practice as specified in ISO 21501-4:2007 .
7.2 Also will be added to Bibliography:
ISO 21501-4:2007 Determination of particle size distribution – Single particle light interaction methods-Part 4: Light scattering airborne particle
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particle light interaction methods Part 4: Light scattering airborne particle counter for clean spaces.
Probable Revisions to ISO 14644-2
New Title for Section:
ISO 14644 2
Cleanrooms and associated controlled environments Part 2: Monitoring toenvironments — Part 2: Monitoring to
provide evidence of performance by ACP
Focus of 14644-2 will be on methods covering it i f ti l d k ti tmonitoring of particles and key supporting parameters
Probable Revisions to ISO 14644-2I t d tiIntroduction
"Thi i i f ISO 14644 2 fl"This revision of ISO 14644-2 reflects a philosophical shift that emphasizes
it i l ifi ti "monitoring over classification."
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Probable Revisions to ISO 14644-2I t d ti
"Thi i i f ISO 14644 2 fl t
Introduction
"This revision of ISO 14644-2 reflects aphilosophical shift that emphasizesmonitoring over classificationmonitoring over classification.
The monitoring process provides a continuingThe monitoring process provides a continuingflow of data over time, offering a greaterassurance of the performance of theassurance of the performance of theinstallation."
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Probable Revisions to ISO 14644-2I t d ti
"Potential benefits gained from more substantial
Introduction
monitoring are:
Faster response to adverse conditions– Faster response to adverse conditions– Ability to Trend data over time– Additional parameters in conjunction with airborne counts– Integration of data from multiple instruments– Enhanced knowledge of installation and process allows
more effective risk analysis– Reduction in operation costs and product losses"
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Probable Revisions to ISO 14644-2I t d ti
"ISO 14644-2 specifies requirements of a monitoring plan,
Introduction
based on a risk assessment of the intended use. The data obtained provides evidence over time of continuing cleanroom or clean zone performance related to airbornecleanroom or clean zone performance related to airborne cleanliness by particles (ACP).
In some circumstances, relevant regulatory agencies may impose supplementary policies or restrictions. In such situations appropriate adaptations of the monitoringsituations, appropriate adaptations of the monitoring procedures may be required."
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Probable Revisions to ISO 14644-2I t d ti
"The level of airborne particles measured under a
Introduction
monitoring plan may typically be higher than the level observed during the at-rest classification process.
The observed values may fluctuate considerably due to factors such as, but not limited to, the number of personnel present, the rate of air flow or exchange, the operation of instruments or machinery, and activities in adjacent spaces "adjacent spaces.
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Probable Revisions to ISO 14644-2I t d ti
"In processes that inherently produce particles as part of
Introduction
the process and where these particles are not a threat to the process or product, it may be appropriate to rely on periodic at-rest classification rather than monitoring ofperiodic at rest classification rather than monitoring of airborne particles in operation. Other performance and cleanliness attributes may still be required to be monitoredmonitored.
After a monitoring plan is initially established, it may be necessary to revise the plan when significant changes y p g gare made to the installation or process requirements. It is also prudent to conduct periodic reviews of a monitoring plan based on data obtained "
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plan based on data obtained.
Probable Revisions to ISO 14644-2T bl f t t
Introduction
Table of contents
1 Scope2 Normative references3 Terms and definitions4 Creating, executing and maintaining a monitoring plan4.1 Principle4 2 Risk Analysis4.2 Risk Analysis4.3 Monitoring plan4.4 Review and approval4.5 Analyzing Data5 Periodic classification
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Probable Revisions to ISO 14644-2T bl f t t
Annex A (informative)
Table of contents
Matters to consider when developing a monitoring planA.1 General ConsiderationsA.2 Pressure differential monitoringA.3 Airborne particle monitoring systemA.4 Airflow velocity and volume monitoring
Annex B (informative) Matters to consider when setting Warning levelsB.1 Setting levelsB.2 Considerations in setting Warning levels for Pressure DifferentialB.3 Consideration in setting Warning levels for Airborne Particle
Counts
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Monitoring
- Environmental
- Process
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Environmental MonitoringMonitoring
Understanding stability of particulate levels through trends
Samples taken daily, weekly or monthly
No requirement to monitor as many points as needed for classification
No requirement to sample 1 cubic meter
Consider using viable sample points as guidance in choosing positions and number of sample points in
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g p p pan area
Process MonitoringMonitoring
In operation or dynamic only
Relates to process and product quality
Data may be needed for product releaseData may be needed for product releaseOften included with Batch Record
Average only count data from same locationAverage only count data from same location– Each point must be below limit– But not necessarily each sample
M b OK d l ALERT ACTION il 3 d 5 h– May be OK to delay ALERT or ACTION until 3rd or 5th consecutive high reading
– Information is about sample point not zone
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CleanroomMonitoringMonitoring
No clear guidance from standards or regulationNumber of sample points– Number of sample points
– Positions of sample points
It is necessary to consider the purpose of monitoring within the specific manufacturing context.– Assess the potential for product exposure– Assess the potential for product exposure– Consider possible contaminants created by process
– Impact to product– Impact to operators– Impact to operators
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CleanroomMonitoring
However two guidances are offered:
Monitoring
US FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing- Sterile Drug Products Produced by Aseptic Processing
EU GMP Annex 1U G e- Manufacture of Sterile Medicinal Products
49
FDA’s Guidance for Industry: Sterile Drug Products g
Produced by Aseptic Processing
Initial release: June 1987
New Revision: September 2004
Restates count values in metric format– Cubic foot cubic meterCubic foot cubic meter– 1 cubic meter = 35.31 cubic feet
Refers to ISO 14644-1Refers to ISO 14644-1– Class 100 > ISO Class 5– Limit restated
3520 counts/m³ for counts 0 5 μm and larger
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3520 counts/m for counts 0.5 μm and larger
FDA’s Guidance for Industry: Sterile Drug Products
F t ti l d t
gProduced by Aseptic Processing
Focus on potential product exposure
Defines two zonesDefines two zones– Critical (similar to Grade A)– Controlled (similar to Grade C or D support areas)
Monitor at 0.5 microns
Sample point location– “Not more than 1 foot away from the work site, within the
airflow, and during filling/closing operations”
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Guidances for Aseptic ProcessingAseptic Processing
Pharmaceutical Industry Compliance GuidanceCompliance Guidance
– FDA cGMP Guidance for Industry• Sterile Drug Products
Produced by Aseptic Processing
– EU GMP Annex I (EMEA)• Manufacture of Sterile
Medicinal ProductsMedicinal Products
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EU GMP Annex 1 is more specificthan FDA cGMP Guidance
Guidances for Aseptic ProcessingAseptic Processing
53
Guidances for Aseptic ProcessingAseptic Processing
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PIC/S Guidance
7. ENVIRONMENTAL AND PERSONNEL MONITORINGAnnex I of the EU/PIC/S Guide to GMP provides the basis
for environmental and personnel monitoring requirements and recommendationsand recommendations.
Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring, intervention monitoring and staff training.
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PIC/S Guidance
7.1 Air Borne Microbial and Non-Viable Particle Monitoring
7.1.1 It is important to state that the monitoring activity itself should not compromise the product quality Worst caseshould not compromise the product quality. Worst case scenarios of simulations tests should also include monitoring activities.
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PIC/S Guidance
7.2 Non-viable monitoring7.2.1 The location chosen for monitoring should be checked
to ensure that the positions reflect the worst case. For room monitoring the counts should be performed inroom monitoring, the counts should be performed in locations where there is most operator activity. For the filling environment the counts should be performed dj h filli d hadjacent to the filling zone and where components are
exposed in such way as to detect operator activity within these areas.
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PIC/S Guidance
7.2 Non-viable monitoring7.2.1 (continued) Monitoring with sampling probes located
in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding thefilter rather than the air immediately surrounding the critical zones should be avoided. However the location of the sample device should not compromise the laminarity f h i fl i h i i l I i i l lid i h ldof the air flow in the critical zone. Initial validation should
be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed q y yduring process simulation tests.
58
EU Annex 1:L t t i i (2009)Latest revision (2009)
Classification– Sections 4 through 7g
MonitoringMonitoring – Sections 8 through 17
59
EU Annex 1 Summary:Cl ifi tiClassification
Classification – Sections 4 through 7Classification – 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 p p
sample volume of 1 m3 should be taken per sample position.
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EU Grade Definitions
Grade Activity 0.5 m 5 m 0.5 mA High Risk - filling, open vials, stopper bowls 3 520 20 3 520 20B Aseptic preparations 3 520 29 352 000 2 000
at rest in operationmaximum permitted number of particles/m3 equal to or above
5 m
• Zone grades according to risk of product contamination
C 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
• Zone grades according to risk of product contamination• Particle count measurements at 0.5 m and 5 m• “At rest” vs “In operation”At rest vs In operation
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EU Annex 1:L i i (2009)
Limits at 5 microns for Grade A
Latest revision (2009)
At Rest In OperationAt Rest In Operation
1 per cubic meter 20 per cubic meter
Grade
At Rest In Operation
Maximum permitted number of particles/m3
equal to or greater than the tabulated sizeGrade
At Rest In Operation
Maximum permitted number of particles/m3
equal to or greater than the tabulated size
0.5 µm 5 µm 0.5 µm 5 µm
A 3 500 1 3 500 1
0.5 µm 5 µm 0.5 µm 5 µm
A 3 520 20 3 520 20
B 3 500 1 350 000 2 000
C 350 000 2 000 3 500 000 20 000
D 3 5000 000 20 000 t d fi d t d fi d
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
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D 3 5000 000 20 000 not defined not definedD 3 520 000 29 000 not defined not defined
EU Annex 1 Summary:Classification
Section 5:Section 5:
“For classification purposes EN/ISO 14644-1 methodology p p gydefines 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 ofof the largest considered particle size and the method of evaluation of the data collected.”
63
EU Annex 1 Summary:Classification
Section 5 (continued)“F l ifi ti EN/ISO 14644 1 th d l“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
• Currently based on SQRT of Area (M^2)
Sample Volume (B,C,D)
• Proposed – Based on lookup table
64
EU Annex 1 Summary: MonitoringMonitoring
Monitoring: Sections 8 through 17Section 8:“Clean rooms and clean air devices should be routinely y
monitored in operation and the monitoring locations based on
a formal risk analysis study– a formal risk analysis study and – the results obtained during the classification of rooms and/or
l d i ”clean devices”
65
EU Annex 1 Summary: Monitoring
Section 9
Monitoring
• “The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions transient events and any systeminterventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded.
= “continuous” !!!
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EU Annex 1 Summary: Monitoring
Section 12:
Monitoring
• “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 forsampling 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
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classification.
Monitoring Positions: Risk-based Approach
Lyo 1Vial
Sterilizing Tunnel
4
51
Tunnel
3
7
2
Lyo 2
6
• Monitoring must follow the workflow, covering areas where product is exposed – Annex 1 (2009)− Where open vials exit de-pyrogenation – human interaction (1)
Lyo 3
− 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
68
g y pproduct is not fully stoppered (6,7)
Monitoring Positions: Risk-based Approach
4
Vial Washing System
1
2 3
In a filling operation for which the final product remains liquid, some points established for a lyophilizedpoints established for a lyophilized product would not be needed.
69
ISO 14644 ISO 21501 dISO 14644, ISO 21501 and EU GMP Annex 1
Sampling of Airborne Particle CountsI A ti M f t i PIn Aseptic Manufacturing Process
70
Air Particle Counter CalibrationISO 21501 and ISO 14644 the link to GMPISO 21501 and ISO 14644 - the link to GMP• Regulators inspect to EU GMP, which
calls up ISO 14644calls up ISO 14644
• Next revision ISO 14644 will refer to ISO 21501-4
• ISO 21501-4 states – “Instruments that conform to this part of ISO 21501 are used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO 14644-1”
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Proposed wording in -1 -2Proposed wording in 1, 2
A.2.2 Airborne particle counter calibrationThe airborne particle counter shall have a valid calibration
certificate; the frequency and method of calibration should be based on current accepted practice as specified in ISObe based on current accepted practice as specified in ISO 21501-4:2007 .
NOTE: Some airborne particle counters cannot be calibrated to all of the required tests in ISO 21501-4:2007.
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ISO 21501-4: Additional Tests
Before ISO 21501-4Si lib ti
ISO 21501-4 Si lib ti• Size calibration • Size calibration
• Verification of size setting• Counting efficiency
• False count rate
• Counting efficiency• Size resolution• False count rate
• Sampling Flow Rate• Concentration limit• Sampling flow rate
• Sampling Time • Sampling time• Sampling volume
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ISO 21501-4 Calibration Standard Delivers:
• Improved compliance– Removes ambiguity by providing a single internationally
recognized standard method for calibrationrecognized standard method for calibration– Harmonization between ISO and GMP guidance
I d it t it d ibilit• Improved unit-to-unit reproducibility
• Improved counting accuracy• Improved counting accuracy
All current Met One particle counters from Hach may
74
be calibrated using ISO 21501-4 at your facility
ISO 21501-4ISO 21501 4What to look for on the calibration certificate
75
ISO 21501-4ISO 21501-4What to look for on the calibration certificate
76
ISO 21501-4ISO 21501 4What to look for on the calibration certificate
“Hach certifies that the calibration performed
complies with thecomplies with the requirements of ISO 21501 .
. .
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Online and Portable Particle CountersPortable Particle Counters
First particle counters designedfor ISO 21501 compliancefor ISO 21501 compliance
MET ONE 3400Cleanroom classification to ISO14644Cleanroom classification to ISO14644
Portable sampling for environmental validationMET ONE 6015PGrade A & B automated monitoring
Internal vacuum pump
MET ONE 6000 MET ONE 7000
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MET ONE 6000Grade A & B automated monitoring
Small and compact
MET ONE 7000Grade A & B automated monitoring
Sealed enclosure for wash downAutomatic vacuum control
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ADDITIONAL INFORMATION
ISO21501@hach.com
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Road Map to ISO 21501-4 compliance
Audit your Methods and Equipment ud you e ods a d qu p e Training
Standard Operating Procedures (SOPs)
Validation (IQ/OQ)
Calibration Policies
Equipment Upgrade as needed
Audit your Calibration Service Factory-trained and authorized
Correct equipment and standards
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Thank you !Thank you !
jgecsey@hach.com
+1 541 210 0194Presented by
Grants Pass, Oregon USA Joe Gecsey
HACH
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Life ScienceApplications
Regulations Concerning Airborne Particle CountingAirborne Particle Counting
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