Professional Documents
Culture Documents
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Theory
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Guidelines
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Monitoring
1
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Agenda
Introduction to Cleanroom Particle Counting
Classification of Air Cleanliness: ISO 14644
Guidance for the Manufacture of Sterile Medicinal Products EU
GMP, Annex 1
Classification
In-Process Monitoring
Best Practices for FMS Solutions
Particle Counter Theory and Calibration: IS0 21501-4
--------
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2
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Agenda
Introduction to Cleanroom Particle Counting
Classification of Air Cleanliness: ISO 14644
Guidance for the Manufacture of Sterile Medicinal Products EU
GMP, Annex 1
Classification
In-Process Monitoring
Best Practices for FMS Solutions
Particle Counter Theory and Calibration: IS0 21501-4
--------
On-line TOC Analyzer
EP&USP Harmonization for Liquid Particle
3
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Why do we care about Particle Counts?
Particles as contamination negatively affect a
process or product
Change chemical composition
Affect stability
Affect purity
Affect safety
Affect reliability
4
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Why do we care about Particle Counts?
Pharmaceutical, Biotechnology
Particles in injection could cause occlusion of
blood vessels
Red Blood cells are about 5 m
Capillary (5 to 10 m)
Large veins (10 to 50 m)
Viables in injection can trigger infection
Possibility of reaction to foreign substances
(RES/allergic reaction)
Medical Devices
Poor adhesion of medicated coating in stent creates
embolisms
5
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Why monitor for particles?
Greatest concern is for viable
microorganisms Technology is not available today to
measure viable counts in real time
Requires incubation time
Total non-viable particle counts
used as a surrogate
Non-viable counts
Includes all types of airborne
material
Solid particles
Fibers
Microorganisms
Skin flakes
100
90
80
70
60
50 Human hair:
Skin Flake:
40 50 -100 m about 20
30 Visible:
m
Bacteria:
20 35 - 50 1 to 8 m
10 m
7
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Relative Sizes of Particles
Pencil cells
8
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Particles Found in a Cleanroom
Aluminosilicate
9
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Guidance Suggested Monitoring
10
9
8
7 Event driven
6
5
Bacterium
4 Baseline
3 2 - 8 m
5 m
2
1 Virus: 0.001 m
0 0.5 m
10
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How an airborne particle counter works
Detector
Particle
Light Trap
Laser Diode
Mirror
12
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Manual Monitoring
Advantages:
- Traditional method of sampling
- Simple
- Flexible
- Low Initial Cost
Disadvantages:
- Inconsistent in Time
- Inconsistent in Position of Probe
- Intrusive to Work Process
- Usually is not continuous
- Production worker often not
informed of high counts
- High Labor cost (labor intensive) 13
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Sequential Monitoring
Advantages:
- Consistently samples fixed positions
- Samples every position one or more
times per hour
- Can operate 24 hours per day
- Frequent sampling of each point
- Consistent sampling position
- Statistical data for historical purposes
- Consistency of data allows SPC analysis
- Can be part of an FMS system
- Single counter to calibrate
A2400
Disadvantages:
- Samples at fixed locations
- Can miss events
- Particle loss in tubing
- Requires auxiliary pump(s) to maintain
constant flow through all sample tubes
R2400
14
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Tubing Transport Loss
15
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Continuous Monitoring
Advantages:
- Able to detect fast, random events
- Uses dedicated counter at each sample point
- Avoids effects of long tubing runs
- Consistent sample points
- All points monitored simultaneously
- Quick operator feedback
- Build statistical database
- Relate particle events to process activity
opportunity to improve process
Disadvantages :
- Requires good plan of monitoring strategy
MET ONE 6000
Sample points must be chosen at the beginning
Decisions must be made about alarms and reports
- More expensive to implement
More instruments
Utility support: data cables, vacuum lines
- Calibration needed for each counter MET ONE 7000
- Data must be processed or summarized 16
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Flexibility Cost Labor
Calibration Quality
100
90
80
70
60
50
40
30
20
10
0
Flexibility Initial Cost Daily Labor Calibration Quality of data
21
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Agenda
Introduction to Cleanroom Particle Counting
Classification of Air Cleanliness: ISO 14644
Guidance for the Manufacture of Sterile Medicinal Products EU
GMP, Annex 1
Classification
In-Process Monitoring
Best Practices for FMS Solutions
Particle Counter Theory and Calibration: IS0 21501-4
--------
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EP&USP Harmonization for Liquid Particle
22
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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-
1999 1
ISO 14644 23
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ISO 14644 General Standard Covers All
Industries
Electronics
Semiconductor
Flat Panel
Circuit Board
Optical
MEMS/Nanomachines
Life Sciences Other
Pharmaceutical Laboratory Electronics
Biotechnology
Medical Devices
Hospitals/Pharmacies
Aerospace Aerospace
Launch Vehicles
Satellites
Commercial/Military Aircraft
Laboratories Life Sciences
Analytical Laboratories
Universities
Other
Nuclear
Photographic, X-ray films
Automobile Painting
24
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Classification Standard
ISO 14644-1
Defines cleanroom classes in a zone
25
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Classification: ISO 14644-1
Minimum number of 1
whichever is
locations greatest
with at least 3 samples
total
26
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Classification Limits ISO 14644-1
ISO 1 10 2
ISO 2 100 24 10 4
27
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What volume do I need to collect?
20 particles
Volume = X 1000 liters
3520 particles
28
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ISO 14644-1 Minimum Sample Time at 1 CFM
Time required (in minutes) at 1 cfm (28.3 lpm) flow rate with 1-minute limit imposed
29
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Continued Compliance:
ISO 14644-2
Maximum Time
Test Parameter Class Test Procedure
Interval
Particle Count
ISO All
5 24
6 Months
ISO 14644-1
Test classes
> ISO 5 12months
Months
Annex A
Important
Air Pressure note: If Particle counts and Differential
ISO 14644-1
All Classes 12 Months
Pressure
Difference are monitored continuously (for Annex B5
example, by a Facility Monitoring System) then
ISO 14644-1
the MaximumAllTime
Airflow Classes
Interval12for
Months
re-certification
Annex B4
can be extended
30
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Example: ISO 14644-1 Classification
Vial
Washing Lyo 1
Station 5m
Lyo 2
8m
5m
Calculations for Number of Points:
Area of clean zone = 80 m
Lyo 3
Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions
4m
31
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Example: ISO 14644-1 Classification
Vial
Washing Lyo 1
Station
1 2 3 4 5 6
Lyo 2
32
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Example
ISO 14644-1 Calculations
1 2 3 4 5 6 7 8 9 10
Vial
Freeze
Washing
Dryer 1
System
Freeze
Dryer 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
the UCL (Upper Confidence Limit). Calculation of
the UCL is only mandated when the number of
positions used is between 2 and 9. Freeze
Best to sample near potential problem spots which Dryer 3
are near entrances and exits and near operator
positions.
33
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Example
ISO 14644-1 Calculations
9
1
Vial 10 Freeze
Washing
8 Dryer 1
System
2
11
3 4 5 6 7
12 Freeze
Dryer 2
Need to adjust for equipment in room.
Under ISO 14644-1, if you sample at 10 or more 13
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. Freeze
14
Best to sample near potential problem spots Dryer 3
which are near entrances and exits and near
operator positions.
34
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Example
ISO 14644-1 Calculations
If the number of points sampled is more than 1 but less than 10,
then the UCL factor must be applied:
a) Calculate the standard deviation
b) Use Students T-factor from tables
c) Calculate UCL
d) Compare to classification limit; UCL must
not exceed the applicable limit
35
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Probable Revisions to
ISO 14644-1, -2
1. Frequency of re-certification
Now:
If zone is ISO Class 5, every 6 months
If zone is ISO Class 6, every 12 months
Proposed:
For all zones, every 12 months
36
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Probable Revisions to
ISO 14644-1, -2
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B.4.1.1
Derive the minimum number of
sampling locations NL from table 3.
38
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ISO
Room Room ISO 14644-1: FS209E FS209E FS209E FS209E
Size Size 14644-1: 2007 Unidirectional Turbulent Turbulent Turbulent
(ft2) (m2) 1999 (95,90) (all classes) Class 1000 Class 10K Class 100K
21.5 2 2 1 2 2 2 2
43.1 4 2 2 2 2 2 2
64.6 6 3 3 3 3 2 2
86.1 8 3 4 4 3 2 2
107.6 10 4 5 5 4 2 2
129.2 12 4 6 6 5 2 2
150.7 14 4 7 7 5 2 2
172.2 16 4 8 7 6 2 2
193.8 18 5 9 8 7 2 2
279.9 26 6 10 12 9 3 2
301.4 28 6 11 13 10 4 2
344.4 32 6 12 14 11 4 2
366.0 34 6 13 15 12 4 2
387.5 36 6 14 16 13 4 2
409.0 38 7 15 17 13 5 2
559.7 52 8 16 23 18 6 2
581.3 54 8 17 24 19 6 2
624.3 58 8 18 25 20 7 2
796.5 74 9 19 32 26 8 3
839.6 78 9 20 34 27 9 3
1033.3 96 10 21 42 33 11 4
1248.6 116 11 22 50 40 13 4
1485.4 138 12 23 60 47 15 5
1894.4 176 14 24 76 60 19 6
2152.8 200 15 25 87 69 22 7
3229.2 300 18 26 130 103 33 11
5382.0 500 23 27 216 171 54 18 39
10763.9
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TOC Analysis
2000 45 29 862 681 216 69
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5000 71 29 2153 1702 539 171
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MET ONE Particle107639.1
Counting 10000 100 29 4306 3404 1077 341
Probable Revisions to
ISO 14644-1, -2
4. Remove possibility to classify
at 5 micron for ISO Class 5
Limit number of 29 removed
Note (b) Due to sampling difficulties affecting collection of large
particles in low concentrations, specification of sampling by DPC
is inappropriate for classification at the indicated class.
40
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Agenda
Introduction to Cleanroom Particle Counting
Classification of Air Cleanliness: ISO 14644
Guidance for the Manufacture of Sterile Medicinal Products EU
GMP, Annex 1
Classification
In-Process Monitoring
Best Practices for FMS Solutions
Particle Counter Theory and Calibration: IS0 21501-4
--------
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EP&USP Harmonization for Liquid Particle
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Guidance for Airborne Particles
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Revisions EU GMP Annex 1 2009
5 particle counts particularly significant when several are seen
consecutively and indicates up to 20/m3 for Grade A and 29/m3 for Grade B
(now equivalent to ISO 5)
Accepts that particle counting may not be possible at the point of fill due to
the generation of particles or droplets from the product itself
At Rest
At Rest In Operation
45
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Intuitive User Interface!
Wizard to conduct pass/fail test for
ISO, EU-GMP, FS and BS standards
Improved area and sample location
management
Easy sampling recipe management
through Group menu
Multiple user level log in for
data security
46
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Intuitive User Interface!
Test wizard for ISO, EU-GMP, FS, and BS standard compliance
Wizard to conduct pass/fail test for ISO, EU-
GMP Annex I, FS 209E and BS5295 standards
No expertise in standards required. Few clicks
to compliance
The wizard guides an operator step by step to
sample data, process data and product reports
47
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Intuitive User Interface!
9
1
Vial 10 Freeze
Filling 8 Dryer 1
Room 2
11
3 4 5 6 7
12
Freeze
Dryer 2
Freeze
14 Dryer 3
48
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Intuitive User Interface!
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Intuitive User Interface!
Location #1
Location #2
50
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Intuitive User Interface!
51
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Met One 3445
3445: 100 LPM Flow Rate
Higher flow rate
Same packaging
Same accessories and support documents
Same battery functionality
Wireless capability maintained
52
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Met One 3445
Rapid classification and routine sampling of Pharmaceutical areas
Battery-powered yet still light-weight
Smooth Stainless Steel enclosure is designed with the needs to
maintain ultra-clean or aseptic areas
Color touchscreen provides a clear window into cleanroom
contamination
Supported by software for stand-alone use and for continuous
monitoring requirements
PortAll 2.4
UVO
EnVigil Lite
OPC Server
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Met One 3445 revised 3400 Datasheet
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Met One 3445 revised 3400 Datasheet
55
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Met One 3445 - Specifications
56
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PortAll Software
Organize, archive and report particle count data
57
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PortAll 2.4 Life Sciences
21 CFR Part 11 Support
Lockout for multiple attempts
Auto Logoff for Inactivity
Password Expiration
Unique User Accounts
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Whats new in PortAll 2.4
Paperless Secure Data Transfer in a 21CFR Part 11 Environment
USB Memory Stick data are now transferred in a binary format
Supports 21CFR Part11 for data security and integrity
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PortAll 2.4 Whats new
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PortAll 2.4 Whats new
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PortAll 2.4 Whats new
Compliance reports stored
in a locked PDF format
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PortAll 2.4 New Data Sheet
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Agenda
Introduction to Cleanroom Particle Counting
Classification of Air Cleanliness: ISO 14644
Guidance for the Manufacture of Sterile Medicinal Products EU
GMP, Annex 1
Classification
In-Process Monitoring
Best Practices for FMS Solutions
Particle Counter Theory and Calibration: IS0 21501-4
--------
On-line TOC Analyzer
EP&USP Harmonization for Liquid Particle
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EU Annex 1 Summary: Monitoring
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.
66
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EU Annex 1 Summary: Monitoring
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 !!!
67
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Monitoring Positions:
Risk-based Approach
Vial
1 Lyo 1
Sterilizing 5
Tunnel 4
2 3
Lyo 2
Monitoring must follow the workflow, covering areas
where product is exposed Annex 1
Where open vials exit de-pyrogenation human interaction (1) 6
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Use Monitoring System for Classification
SAVE TIME!
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Placement of Sample Probes
Annex 1: No guidance
FDA: Sample near to exposed product
Generally near work height and exposed product
If liquid sterile fill, guidance is to sample air approaching the product within 12 (30 cm) of
exposed
71
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Sampling Probes and Mounting
Unidirectional air bathing
the exposed product during
manufacturing
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Where to Monitor?
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Positioning the Probes
Turntable
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Positioning the
Probes Filling Line
<305mm
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Positioning the Probes
Stoppering Station
<305mm
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Monitoring Powder Fill
Section 9:
For Grade A zones, particle monitoring should be undertaken for the
full duration of critical processing, including equipment assembly,
except where justified by contaminants in the process that would
damage the particle counter or present a hazard, e. g. live organisms
and radiological hazards.
In such cases monitoring during routine equipment set up operations
should be undertaken prior to exposure to the risk. Monitoring during
simulated operations should also be performed.
77
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Interference from Product
(Powder Filling)
Exposed product or
vials/ampoules
Sample probe to
demonstrate air
quality before filling
process
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Recommendations
Powder Fill Line
Outfeed
from
tunnel
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System Overview
Multiple Pumps
230VAC
24Vdc
PSU
Vacuum Pump Vacuum Pump
Ceiling void
Remote APC
in Enclosure
WiFi capable 81
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System Overview
Central Vacuum
24 VDC Vacuum Ring Main
Pump
Control
Host RS485,
ethernet
Remote APC in
Enclosure
WiFi capable
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System Overview
230VAC
Integrated Pumps
Host PC
24VDC
24VDC 24VDC 1 A PSU
6A PSU 6A PSU
Ceiling void
Production Area
Prep area Filling Vial capping
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Maintaining Compliance
Early detection of out of compliance
Walking window technique
x x 0 0 0 0 0 0 0 0 0 0 0 1 0 1 x x
36 rolling samples
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Software
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Human Machine Interface
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Real Time Trending
z Trends provide multiple traces, multiple Y axes, real time and historic switching
with alarm limits
zCursor provides analysis features to read actual point values, min,max etc
88
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Historic Trending
zCalendar date entry enables user to select start and stop date required
zCursor allows trace values to be read, traces and alarm levels may be
switched on/off. Up to six signature boxes for sign off. 89
Market Leader in
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Leader in Airborne
MET ONE Particle Counting
Alarm Handling
Alarms can be manually or automatically acknowledged and are
time and date stamped on generation, acknowledgement and clearing
down.
90
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Alarm Reconciliation
92
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Introduction to MET ONE 6000 Series
Multi-color status
indicator LED
0.2 m minimum sensitivity Relative Humidity-Temperature Service port for instrument set-up
Long Life Laser probe connection Also used for remote indicator light stack
Improved Sensitivity
Flexible Communications
Multiple Installation Options
Enhanced Instrument Diagnostics
Long Life Laser Diode
Worldwide service and support
94
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MET ONE Particle Counting
Improved Sensitivity and
Long Life Laser
Identify smaller particles reliably and accurately that could potentially
improve product quality and yield with a sensitivity range of
0.2 to 5.0 m
0.5 to 10.0 m
The Long Life Laser with improved MTTF reduces overall cost of
ownership
Design for Electronics application OR Life Science application (if
sensor installed outside cleanroom)
95
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MET ONE Particle Counting
Flexible Communications
Save FMS integration costs, repair and inventory related costs with multiple
communications
Serial I/O (Pulse, RS-232, RS-485 with Modbus RTU or FX protocol)
Ethernet
Analog
Wireless
97
ANATEL
Market Leader in
TOC Analysis
Bottom vacuum connection
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Installation Options - Mounting
Various mounting options offer
shorter installation and removal time
99
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MET ONE Particle Counting
Introduction to MET ONE 7000 Series
RJ 45 sealed connector
for Ethernet, RS485 serial or
Analog I/O
Makes integration to any FMS easier
101
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MET ONE Particle Counting
Ease of Installation Features
Easy installation with AC or DC input power options
100~230 VAC 50/60 Hz house power
24 VDC local power network
AC or DC input power
option
Makes installation easier
DIP switch for setting
address of
RS485 serial I/O instrument
Makes installation and removal easier
102
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MET ONE Particle Counting
Ease of Installation Features
Wall plate for terminating end-user cables Wall Plate - Front
and tubing, reduces disruption to Makes installation and
removal of counter easier
2 Mounting Plate
5 Wall Plate
7 Power Cable AC or DC
104
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MET ONE Particle Counting
Enhanced Instrument Diagnostics
Built in or optional remote
multi-color status
indicator LED
Enhanced diagnostics reduce trouble shooting time and
downtime
Instrument can be diagnosed for flow,
sensor, communication failures, and
count alarm or count alert through
built-in or external light stack
One short flash, one long flash Blue = Flow Fail (set by software or internal)
One short flash, one long flash Blue = Flow Fail (set by software or internal)
107
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MET ONE Particle Counting
Local Setup Screen Capture
108
Market Leader in
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MET ONE Particle Counting
LAN Setup Screen Capture
109
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Data Display Screen Capture
110
Market Leader in
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MET ONE Particle Counting
Environmental Sensors
Measurement of Temp/RH, Differential Pressure, Air Flow
and Temperature of Fridges, Freezers and Incubators
Differential
Pressure
Sensor
Temp/RH
Sensor
111
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Environmental Sensors
112
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Alarm Indication
113
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MET ONE Particle Counting
Alarm Indication
Delivered where it is needed
Red/Green lamps at each point of fill
Alarm Message displays in area
Computer screen in clean area
114
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Alarm Message Display
zAlerts staff within facility that monitored parameters are out of limits
zFour line LCD display shows local parameters currently in alarm
zBuilt - in Sounder announces arrival of new alarm conditions
zLocal Mute Button, silences sounder without leaving the room
116
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Scalable Software Solutions
For small FMS systems using only Met One 6000/7000 (best at < 20
counters), Pharmagraph enVigil-Lite provides an easy-to-implement
solution
117
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Low-cost, Simple enVigil Lite 2
for Aseptic Production Monitoring
Ethernet
RS-485
118
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Large, Customized, Batch-Driven UVO Systems
for Aseptic Production Monitoring
Client # 1 Client # 2
Fill Line A Fill Line B
Ethernet
RS-485
Server/client with
database
Fill
Line A
Fill Line
B
119
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
OPC Server for Aseptic Production
Sensor network
Sensor Control
Sensors controlled via
Customer Real-time data & control & OPC Server MODBUS / TCP
Software
(SCADA,
UVO, etc.)
Historical electronic data Database Data from sensors configured
for online operation
Paper data & PDF files Crystal Data from sensors configured
Reports for offline portable operation
122
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Table: Sampling Strategies based on
ISO 14644 and EU GMP Annex 1
Grade Classification Regular EM Program Process Monitoring
1. Frequency = 6 months 1. Frequency = a/r (daily ????) 1. Continuous during
2. Minimum number of 2. a/r; sometimes based on process
sample positions: ISO Minimum number of sample 2. Key high risk positions
14644-1 = SQRT area positions: ISO 14644-1 = SQRT 3. No minimum volume
3. Minimum sample volume: area defined
Annex 1 = 1 cubic meter 3. Minimum sample volume: a/r
A
4. best practice: (3) 1-minute
counts
a/r = as required
123
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MET ONE Particle Counting
Table: Sampling Strategies based on
ISO 14644 and EU GMP Annex 1
Grade Classification Regular EM Program Process Monitoring
a/r = as required
124
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MET ONE Particle Counting
Regulations and Guidance for the
Manufacture of Sterile Medicinal
Products ISO 14644 and EU GMP
Annex 1
125
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Particle Count Theory and
Calibration (ISO 21501)
126
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MET ONE Particle Counting
Agenda
Introduction to Cleanroom Particle Counting
Classification of Air Cleanliness: ISO 14644
Guidance for the Manufacture of Sterile Medicinal Products EU
GMP, Annex 1
Classification
In-Process Monitoring
Best Practices for FMS Solutions
Particle Counter Theory and Calibration: IS0 21501-4
--------
On-line TOC Analyzer
EP&USP Harmonization for Liquid Particle
127
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MET ONE Particle Counting
Optical Particle Sensor Configuration
128
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MET ONE Particle Counting
Sensor View Volume
The View Volume is
The area where the
air stream and the
Inlet Tube laser beam intersect
Requires:
Even illumination
Precise alignment
129
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MET ONE Particle Counting
Particle Sizing
130
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MET ONE Particle Counting
Counting Electronics
+V
Analog Signal in
+V
CH. 3
CH. 2 CH1
CH. 1
131
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MET ONE Particle Counting
Air Particle Counter Calibration
ISO 21501 and 14644 - the link to GMP
Regulators inspect to EU GMP,
which calls up ISO14644
Next revision ISO14644 will refer to
ISO21501-4
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
132
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What is ISO 21501?
133
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MET ONE Particle Counting
What is ISO 21501 replacing?
134
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MET ONE Particle Counting
ISO 21501 Additional Tests
Maximum particle Particles per cubic Particles per cubic Particles per cubic 10% Coincidence loss (calculated)
concentration centimeter centimeter meter (minimum size) On screen calculator
136
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Calibrating Air Counters with
PSL Spheres
f
Mean size
Std Deviation
size
NIST-traceable standard particles
have normal distribution
137
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Particle Count Distribution
Number of Particles
Market Leader in
millivolts (Particle Size) 138
Particle size
0.3 m 0.5 m
Particle size
0.3 m 0.5 m
Poor resolution leads to poor counting accuracy:
undercounting in smaller sized channels 140
Market Leader in
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Counting Efficiency ISO 21501
At the counter minimum Using PSL that is 1.5 2 times
specified size the minimum specified size
AND
Channel 1 Channel 1
The counting efficiency for PSL particles of the minimum measurable particle size value
marked in the specifications shall be within the range from 30% to 70%
AND
PSL particles of 1.5 2 times minimum measurable particle size shall be 90% to 110%
141
Market Leader in
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Illumination Uniformity
Affects Resolution
Laser beam in cross section
Particle =
Ideal: Even illumination in the view volume provides the same pulse
height regardless of where the particle passes through the beam
=
Not ideal: Uneven illumination causes pulse height variance. High
illumination intensity leads to high intensity peak, and low intensity
illumination leads to low peak height
142
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MET ONE Particle Counting
Effects of Flow Rate
on Pulse Height
The amplitude of the sensor output is a function of the particles
residence time in the view volume.
145
Market Leader in
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Leader in Airborne
MET ONE Particle Counting
Hach Ultra and ISO 21501 Designed
Compliant Instruments:
147
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MET ONE Particle Counting
Core Cal 3 Features Continued
Automatic counter detection
Real-time graphing capability
148
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Professional Documentation
Professional Abobe PDF certificates
Custom logo capable
Incorporated into Hach calibration procedures
149
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Competitors 100 lpm
PHA Curve (0.5 um)
Poor optical performance
leads to very poor
resolution
This particle counter does not meet the JIS 9921 or ISO 21501
standard for counting efficiency
150
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Ultra High Flow Considerations (100 lpm)
151
Market Leader in
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Leader in Airborne
MET ONE Particle Counting
Sampling Probes and Mounting High-Flow
Unidirectional air bathing
the exposed product during
manufacturing
152
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Effect of Exhaust Air:
Issues in using High-Flow
REMEMBER:
There is no
requirement to
sample 1m3 of air
when monitoring
All current Met One particle counters from Hach may be calibrated using ISO
21501 at your facility
155
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
MET ONE Portfolio
156
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Total Organic Carbon
157
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Why?
Regulation
TOC toUSP<643>, EP 2.2.44
Conductivity to USP<645>, EP 2.2.38
Suitable for WFI and PW
Water contamination
Biofilm
158
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
TOC increase and Biofilm
159
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Correlation between
endotoxines and TOC
160
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
On-line vs. conventional
lab testing
161
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Anatel Theory
162
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
USP <643> & EP 2.2.44
Requirements
Attribute USP <643> EP 2.2.44
163
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MET ONE Particle Counting
USP <643> & EP 2.2.44
Requirements
Limit of detection 0.05 mg of carbon per liter 0.05 mg of carbon per litre
164
Market Leader in
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MET ONE Particle Counting
USP <643> & EP 2.2.44 Requirements
Attribute USP <643> EP 2.2.44
System periodically demonstrated at suitable intervals
Suitability
frequency
Response RE = 100[(rss rw)/(rs rw] not less RE = 100[(rss rw)/(rs rw] not less
Efficiency than 85% and not more than 115% than 85% and not more than 115%
System suitability SOPs should System suitability SOPs should
include error trapping for systematic include error trapping for systematic
errors. errors.
Limit response rs rw limit response (not necessarily rs rw limit response (not necessarily
500 ppb) 500 ppb)
165
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MET ONE Particle Counting
USP <643> & EP 2.2.44
Requirements
On-line locations reflect the quality of the water used. representative of the water used.
(changed from earlier draft specifying
quality of the water at the use
points)
166
Market Leader in
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Leader in Airborne
MET ONE Particle Counting
Anatel Theory
167
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Anatel Theory of Operation
168
Market Leader in
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MET ONE Particle Counting
Principle of operation
conductivity
UV on Time
169
Market Leader in
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Product Portfolio Positioning
Anatel TOC
Pharmaceuticals Electronics
PAT700 A1000XP
A643a
A1000
170
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Leader in Airborne
MET ONE Particle Counting
Anatel Performance Criteria
171
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
A643 overview
172
Market Leader in
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Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PAT 700
173
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Using On-line TOC analyzers to Meet USP <643>
TOC and <645> Conductivity
Process piping
Isolation
valve
Drain
174
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PAT 700 Key features - Video
175
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PAT700 TOC Analyzer with OASIS
TM
176
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PAT700 TOC Analyzer with OASIS
TM
-Reduces risk
Information about each standard stored in RFID (Radio Frequency
Identification) tag on the bottle (concentration, C of A value, lot number, expiration
date )
177
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
OASIS Technology - RFID
TM
179
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
UV DetectTM Diagnostics
180
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Integral Color touch screen
181
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
PAT700 Portable or Stationary
Optional handle sold separately
Customer installed
Recommended to be used with quick
connect version of analyzer
182
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MET ONE Particle Counting
reflect the quality of the water used
Points
Water Of
Purified
treatment Use
Water
plant
Tank
Points
Of
WFI Use
treatment WFI
plant Tank
183
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Cleaning in Place Validation
Typical Process:
Rinse vessel
Grab samples
Perform laboratory with TOC HPLC
Drawback
Labor intensive
Material intensive
Slow process
Vessel being cleaned unavailable.
184
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Cleaning in Place Validation
TOC & Conductivity
Conductivity/TOC Process:
Rinse vessel
Monitor conductivity
When conductivity reach a low level, start
TOC
Valid CIP after TOC reach low value
Advantage
PAT
Quick answer
Lab independent
185
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
186
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Cleaning in Place Validation
TOC & Conductivity
187
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Cleaning in Place Validation
TOC & Conductivity
Conductivity
TOC
Time
Stop CIP
Final Rinse Start TOC measure
188
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Lab move to online TOC
189
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Total Organic Carbon
190
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Liquid Particle Counting
191
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Effects of Particulate Contamination
Possibility of reaction to
foreign substances
(RES/allergic reaction)
192
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Global Regulations:Particles in
Liquids
Primary method
Optical Particle Counter [OPC]
Light Obscuration Counter
Secondary method
Optical microscope
Subjective
Labor intensive
Requires more time to process samples
193
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Volume Definitions: SVI, LVI
194
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Global Regulations: Particles
in Liquids
195
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Global Regulations: Particles in Liquids
196
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Harmonization of USP 788 with EP
197
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Harmonization of USP 788
198
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Comparison of Compendial Requirements for Liquid Particles in Injections
200
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Ophtalmic products
USP <789>
Title: Particulate Matter in Ophthalmic Solutions
Based on methods and standardization tests of USP <788>
Increases particulate matter limits for ophthalmic solutions
50 or fewer particles of 10 micron or larger
5 or fewer particles of 25 micron or larger
Excludes these formulations from particulate testing
Gels
Suspensions
Emulsions
Medical devices
EP
By microscope only, and only for eye-drops:
No more than 20 particles 25 microns and larger
No more than 2 particles 50 microns and larger.
No particles greater than 90 microns. [Refer to General section, 1163, Eye Preparations].
201
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MET ONE Particle Counting
Calibration & System Suitability
202
Market Leader in
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
Calibration & System Suitability
203
Market Leader in
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Calibration & System Suitability
204
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MET ONE Particle Counting
Calibration & System Suitability
USP <788> 32
Harmonized with EP & JP
- Calibration with Particle Sphere Latex (sizes between 10
and 25m)
- System Suitability with USP Particle Count RS
205
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Calibration & System Suitability
Hach recommendation
Calibration + IST every 6 months (Sample Volume accuracy;
Sample Flow Rate; Calibration; Sensor Resolution; Particle
Counting Accuracy USP Particle Count RS)
206
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PharmSpec 2.2 Software
Added USB to connect 9705 to
computer
Supports 21 CFR Part 11
compliance
Familiar environment minimizes
learning curve and training time
Network backup and archiving
Designed for Windows 2000 and
XP
Create and control user-defined
tests
207
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PharmSpec 2.2 Software
208
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
PharmSpec 2.2 Software
HIAC
Global Innovator in
Fluid Particle Applications -Electronic resolution
Leader in Airborne
MET ONE Particle Counting
PharmSpec 2.2 Software
Permits users
to comply
with FDA 21
CFR Part 11 -
Electronic
Records,
Electronic
Signatures
210
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Update for PharmSpec
http://www.hachultra.com/index.php/hachultra/tools/downloads/pharmspec_2_0_downloads
211
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Product Portfolio Positioning
212
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
9705 Features: Sides
Handles
Easily moved
Sensor Cleanout
Quick access for removing blockages
Thermal printer
Delivers data immediately
Counts
Averages
Standard Deviation
Software for computer PHARMSPEC
Include all EP & USP procedure test
User procedure builder
IQ/OQ doc
213
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Liquid Particle Counting
214
Market Leader in
ANATEL TOC Analysis
Global Innovator in
HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting