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1Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Particle Counting-
Theory-
Guidelines-
Monitoring
2Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
3Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
4Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
• Contamination affects the “yield” of a process– Increases cost to produce– Increases cost to maintain or service– Increases “cost of ownership” [COO]– Decreases ROI of capital equipment purchase
5Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Why do we care about Particle Counts?• Pharmaceutical, Biotechnology
– Particles in injection could cause occlusion of blood vessels
• Red Blood cells are about 5 µm• Capillary (5 to 10 µm) • Large veins (10 to 50 µm)
– 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
• Medical and photographic films– Contamination prevents complete image recovery
6Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Why monitor for particles?
• 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
• Non-viable particle counting offers potential for real-time response
Greatest concern is for viable microorganisms
Non-viable particle count monitoring is a critical component of the total Environmental Monitoring program
7Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
0102030405060708090
100
Relative Sizes of Particulate Matter
Human hair: 50 -100 µm
Visible: 35 - 50
µm
Bacteria: 1 to 8 µm
Skin Flake: about 20
µm
8Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Table salt
Pencil cells
Bacteria
Relative Sizes of Particles
9Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Particles Found in a Cleanroom
Aluminosilicate
10Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Guidance Suggested Monitoring
0123456789
10
Bacterium
2 - 8 µm
0.5 µm
Virus: 0.001 µm
5 µm
“Event” driven
Baseline
11Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
How an airborne particle counter works …
Laser Diode
Detector
Mirror
Particle
Light Trap
Principle: Light Scattering
12Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Three Common Methods of Sampling
• Manually with a handheld or portable particle counter• Sequentially with a manifold/scanner and particle counter• Continuously with portable or remote particle counters
MET ONE 6000 & 7000 Seriesfor production monitoring Grade A & B areas
MET ONE 3400 SeriesCleanroom classificationEnvironmental monitoringShort-term online sampling
MET ONE HHPCHandheld particle counterUsed for troubleshooting
13Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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)
Manual Monitoring
14Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
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
A2400
Sequential Monitoring
15Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Tubing Transport Loss
16Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
Sample points must be chosen at the beginningDecisions must be made about alarms and reports
- More expensive to implementMore instrumentsUtility support: data cables, vacuum lines
- Calibration needed for each counter- Data must be processed or summarized
MET ONE 6000
MET ONE 7000
Continuous Monitoring
17Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Flexibility Cost Labor Calibration Quality
0
10
20
30
40
50
60
70
80
90
100
Flexibility Initial Cost Daily Labor Calibration Quality of data
Manual Sequential Continuous
18Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Cleanroom and Clean Zone ClassificationClassification is the formal process of qualifying the environment by the number of particles using a standard method (ISO 14644)
– Performed on a regular basis but not frequently• Grade A areas: Six months, “ISO 4.8”• Grade B areas: Six months, ISO 5 • Grade C, D areas: Annually, ISO 7/8
– Standards define minimum number of points• Based on area of cleanroom or clean zone
– Standards define minimum amount of air to be sampled
• Minimum volumes for statistically valid samples (typically 1 minute at 1 cfm)
• Grade A requires minimum 1 m3 (Annex 1)
Classification is a rigid protocol
19Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Environmental Monitoring
• Number of sample points defined by risk assessment
– Area of cleanroom or clean zone– Activity to be performed– Risk to product
• Frequency and volume of sample points defined by risk assessment
– Frequent enough to show control– Frequent enough to manage risk of product contamination
Inferred guidance, not rigid by regulation
• Determine readiness of room to carry out designated task
• Performed whenever relevant activity will occur – daily work
Typically performed with portable counters
20Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Aseptic Process Monitoring
• Governed by EMEA and FDA Guidance– Augments ISO 14644 requirements for critical (Grade
A) areas– Recommends continuous monitoring
• Number of sample points based on risk assessment – Not rigidly defined by guidance
• Location of points based on risk assessment– Limited guidance on sampling location
• Sample volumes defined by type of equipment
Published guidance, not rigid – company specific SOPs
21Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Regulations and Guidance for the Manufacture of Sterile Medicinal Products ISO 14644 and EU GMP
Annex 1
22Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
23Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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 Air Monitoring Standards
ISO 14644
1999
24Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
ISO 14644 General Standard Covers 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
25Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Classification Standard ISO 14644-1
• Defines cleanroom classes in a zone
• Establishes minimum sampling volumes – 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
26Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Classification: ISO 14644-1
2.0 liter
1with at least 3 samples
total
Minimum sample volume
Minimum sample time 1 minute
Minimum number of locations
A sample size with at least 20 theoretical particles, or
whichever is greatest
27Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Classification Limits ISO 14644-1
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
28Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
What volume do I need to collect?
• ISO 14644 requires sample with 20 theoretical particles
• ISO 14644 allows 3520 particles (0.5um) in 1m3 (1000 liters)
20 particles3520 particlesVolume = X 1000 liters
Volume = 5.7 litersGreater than 2.0 liters so minimum sample volume is satisfied
29Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um
ISO Class 1 70.64 353.20
ISO Class 2 7.06 29.43 70.64 176.60
ISO Class 3 1.00 2.98 6.93 20.18 88.30
ISO Class 4 1.00 1.00 1.00 2.01 8.51
ISO Class 5 1.00 1.00 1.00 1.00 1.00 24.36
ISO Class 6 1.00 1.00 1.00 1.00 1.00 2.41
ISO Class 7 1.00 1.00 1.00
ISO Class 8 1.00 1.00 1.00
ISO Class 9 1.00 1.00 1.00
30Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Continued Compliance: ISO 14644-2
Schedule of Tests to Demonstrate Continuing Compliance
Test Parameter Class Maximum Time Interval Test Procedure
Particle Count Test
≤ ISO 5 6 Months ISO 14644-1 Annex A> ISO 5 12 Months
Air Pressure Difference All Classes 12 Months ISO 14644-1
Annex B5
Airflow All Classes 12 Months ISO 14644-1 Annex B4
Important note: If Particle counts and Differential Pressure are monitored continuously (for example, by a Facility Monitoring System) then the Maximum Time Interval for re-certification can be extended
24months
All classes
31Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Example: ISO 14644-1 Classification
Lyo 1
Lyo 2
Lyo 3
Vial Washing Station
8 m
4 m
5 m
5 mCalculations for Number of Points:
Area of clean zone = 80 m²
Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions
32Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Example: ISO 14644-1 Classification
Lyo 1
Lyo 2
Lyo 3
Vial Washing Station
1 2 3 4 5 6
7
8
9
Calculations for Number of Points:
Area of clean zone = 80 m²
Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions
33Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
FreezeDryer 1
FreezeDryer 2
FreezeDryer 3
Vial Washing System
• 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.
• Best to sample near potential problem spots which are near entrances and exits and near operator positions.
1 2 3 4 5 6 7 8 9 10
ExampleISO 14644-1 Calculations
34Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
FreezeDryer 1
FreezeDryer 2
FreezeDryer 3
Vial Washing System
• 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.
• Best to sample near potential problem spots which are near entrances and exits and near operator positions.
1
2
3 4 5 6 7
8
9
10
11
12
13
14
ExampleISO 14644-1 Calculations
35Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
ExampleISO 14644-1 Calculations
1. Average sample data values at each position2. Normalize the average to number of particles per cubic meter3. Compare normalized value to the target class limit; normalized value
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 10,then the UCL factor must be applied:
a) Calculate the standard deviationb) Use Student’s T-factor from tablesc) Calculate UCLd) Compare to classification limit; UCL must
not exceed the applicable limit
36Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Probable Revisions to ISO 14644-1, -2
1. Frequency of re-certificationNow:
• 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
37Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Probable Revisions to ISO 14644-1, -2
2. Eliminate Student’s T test for sample plans with 1 to 9 sample positions
3. Method of determining number of sample positions– Replace 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 points
38Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
B.4.1.1
Derive the minimum number of sampling locations NL from table 3.
Table 3 shows 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.
Different levels of confidence and verification can be specified and agreed upon by the customer and supplier.
39Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Room Size (ft2)
Room Size (m2)
ISO14644-1:
1999
ISO14644-1:
2007(95,90)
FS209EUnidirectional(all classes)
FS209ETurbulent
Class 1000
FS209ETurbulent
Class 10K
FS209ETurbulent
Class 100K21.5 2 2 1 2 2 2 243.1 4 2 2 2 2 2 264.6 6 3 3 3 3 2 286.1 8 3 4 4 3 2 2
107.6 10 4 5 5 4 2 2129.2 12 4 6 6 5 2 2150.7 14 4 7 7 5 2 2172.2 16 4 8 7 6 2 2193.8 18 5 9 8 7 2 2279.9 26 6 10 12 9 3 2301.4 28 6 11 13 10 4 2344.4 32 6 12 14 11 4 2366.0 34 6 13 15 12 4 2387.5 36 6 14 16 13 4 2409.0 38 7 15 17 13 5 2559.7 52 8 16 23 18 6 2581.3 54 8 17 24 19 6 2624.3 58 8 18 25 20 7 2796.5 74 9 19 32 26 8 3839.6 78 9 20 34 27 9 31033.3 96 10 21 42 33 11 41248.6 116 11 22 50 40 13 41485.4 138 12 23 60 47 15 51894.4 176 14 24 76 60 19 62152.8 200 15 25 87 69 22 73229.2 300 18 26 130 103 33 115382.0 500 23 27 216 171 54 18
10763.9 1000 32 28 431 341 108 3521527.8 2000 45 29 862 681 216 6953819.6 5000 71 29 2153 1702 539 171107639.1 10000 100 29 4306 3404 1077 341
40Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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.
5. Indicate that single digit limits for ISO Class 1 and 2 create challenges to timely execution
41Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
42Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Guidance for Airborne Particles
Pharmaceutical Industry Compliance Guidance
– FDA cGMP Guidance for Industry• Sterile Drug Products Produced by
Aseptic Processing
– EU GMP Annex I (EMEA)• Manufacture of Sterile Medicinal
Products
EU GMP Annex 1 is more rigidthan FDA cGMP Guidance
43Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
EU GMP Annex 1 - 2003
• Emphasizes continuous monitoring for Grade A and recommends for Grade B areas– “A continuous measurement system should be
used for monitoring the concentration of particles in the Grade A zone, and is recommended for the surrounding Grade B areas.”
• Introduces concept of measuring one cubic meter for “routine testing” (Meaning: classification, not in-process monitoring)
From EU Annex 1“The guidance has been reviewed in the light of the international standard EN/ISO 14644-1 and amended in the interests of harmonisation but taking into account specific concerns unique to the production of sterile medicinal products.”
44Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Revisions EU GMP Annex 1 2009• 5μ 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
• Clearly differentiates classification and 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 for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.”
- 1minute sampling time for continuous monitoring
- 1m3 for classification
45Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Grade Maximum permitted number of particles/m3 equal to or above
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
EU GMP Annex 1 Revised: 1 March 2009
Grade Maximum permitted number of particles/m3 equal to or above
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
Limits at 5 microns for Grade A1 per cubic meter 20 per cubic meter
46Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
47Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
48Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Intuitive User Interface!
Better area/location management
• Multiple locations with unique location ID and repeatable location name can be created
• A group of locations can be assigned to a larger cleanroom space called an ‘area’
• Location setting can be copied
FreezeDryer 1
FreezeDryer 2
FreezeDryer 3
Vial Filling Room
1
2
3 4 5 6 7
8
910
11
12
13
14
49Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Intuitive User Interface!
Better area/location management
3400 # 1 3400 # 2 3400 # 3
50Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Intuitive User Interface!
Better group management
• Group is a collection of desired sampling parameters• New group can be created or existing group can be loaded• A location can be added to or removed from a group• ‘Settings’ button allows pre-selecting sampling parameters
such as sampling time, delay, hold time, count and environmental alarm, etc.
Group = Sampling Recipe
Group is a collection of pre-set sampling
parameters and alarmlimits
Location #N
Area #1
Location #1Location #2
Location #3Location #4
Individual Location setting
51Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Intuitive User Interface!
21 CFR Part 11 compliance: unique user log in
• Multiple level of user accounts – Basic (no log in)– Operator– Administrator
• No limits to number of log in accounts• An administrator can create operator level user
account and assign selective access rights and group access
52Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Met One 3445
• 3445: 100 LPM Flow Rate– Higher flow rate– Same packaging– Same accessories and support documents– Same battery functionality– Wireless capability maintained
• Meets ISO 21501-4– Resolution– Sensitivity
53Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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
54Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Met One 3445 – revised 3400 Datasheet
55Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Met One 3445 – revised 3400 Datasheet
56Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Met One 3445 - Specifications
57Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
PortAll Software Organize, archive and report particle count data
• Download Utility for Airborne Particle Counters
• Two Versions– Generic Industries– Life Science
• Demo version provided with all portable and handheld counters– 30-day operation– Can shift or upgrade License type
• Generate Spreadsheets and Graphs of Data
• Generate reports based on Standards/Guidances– ISO 14644– FS209E– EU GMP Annex 1
58Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
PortAll 2.4 – Life Sciences
• 21 CFR Part 11 Support– Lockout for multiple attempts– Auto Logoff for Inactivity– Password Expiration– Unique User Accounts
• Satisfy Corporate standards– Length of User Name– Length of Password
• Audit Trail of User actions
59Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
What’s 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
• Report Generation Just Got Easier– Report wizard now fully supports EU GMP Annex 1 reporting
• Secure, Paperless Compliance Reports– Export and archive electronic reports in a secure PDF format
• No Need to Bring Laptops into the Cleanroom– Leverage your existing company network to transfer data– Ethernet, wireless and serial communications networks fully supported
60Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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PortAll 2.4 – What’s new
Support for USB Memory Stick transferBinary format cannot be edited
Only recent “Raptor” versions of 3400
61Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
PortAll 2.4 – What’s new
• Crystal Reports engine– Standard reports– Custom by user– Custom by Systems Group
• New! EU GMP Annex 1 report
62Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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PortAll 2.4 – What’s new
• Compliance reports stored in a locked PDF format
• Suitable for archive in LIMS or other data management system
• Fully supports 21 CFR 11
63Market Leader in TOC AnalysisANATEL
HIACMET ONE
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PortAll 2.4 – New Data Sheet
64Market Leader in TOC AnalysisANATEL
HIACMET ONE
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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
65Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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.”
Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009
• 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.
66Market Leader in TOC AnalysisANATEL
HIACMET ONE
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EU Annex 1 Summary: Monitoring
Section 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”
Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009
67Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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.
Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009
= “continuous” !!!
68Market Leader in TOC AnalysisANATEL
HIACMET ONE
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Monitoring Positions: Risk-based Approach
Lyo 1
Lyo 2
Lyo 3
VialSterilizing
Tunnel
3
45
6
7
1
2
• Monitoring must follow the workflow, covering areas where product is exposed – Annex 1
— 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)
69Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Use Monitoring System for Classification
Add a wireless portable for room classification
Reduce the number of manually monitored classification points
SAVE TIME!
70Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
71Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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
Sample near to points of intervention by operatorsExamples: • Descrambler table• Filling needles• Stoppering process
Less than 1 foot (12 inches or 30 cm)
72Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Sampling Probes and Mounting
Isokinetic sample probe for particle monitoring (not positioned directly over exposed product)
Exposed product or vials/ampoules
Unidirectional air bathing the exposed product during
manufacturing
73Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Where to Monitor?
74Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Positioning the Probes Turntable
Probe shown with Cap in place
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HIACMET ONE
Global Innovator in Fluid Particle Applications
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Positioning the Probes Filling Line
<305mm
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HIACMET ONE
Global Innovator in Fluid Particle Applications
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Positioning the ProbesStoppering Station
<305mm
77Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
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.
Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009
78Market Leader in TOC AnalysisANATEL
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Interference from Product (Powder Filling)
Exposed product or vials/ampoules
Unidirectional air bathing the exposed product during
manufacturing
Higher sample probe for monitoring during
production
Sample probe to demonstrate air
quality before filling process
79Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Recommendations Powder Fill Line
Inlet HEPA Filter
Outfeed from
tunnel
= Position of monitoring during filling = Positions of monitoring ‘at rest’
80Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Continuous Monitoring
• An FMS System can monitor:– Airborne particulates, – Room pressures and air flow– Room temperature and humidity– Other parameters such as door interlocks, etc
• System configurations available:– Multiple Pumps: Multiple sampling positions, greatest flexibility/redundancy, but
higher install cost
– Central Vacuum: Multiple sampling positions, good flexibility/redundancy and medium install cost
– Integrated Pumps: Multiple sampling positions, good flexibility/redundancy and lowest install cost
81Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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System Overview –Multiple Pumps
Host RS485, ethernet
230VAC
Vacuum Pump Ceiling void
Clean room
Vacuum Pump
Pump Controller
With Flow sensor
Pump Controller
With Flow sensor
24Vdc PSU
Wall PlatePortable APC
Remote APC in Enclosure
Computer with FMS Software
WiFi capable
82Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
System Overview –Central Vacuum
Host PC
Host RS485, ethernet
24 VDC
Plant room
Clean room
Smart Socket Controller, Flow sense
and vacuum control valve
Smart Socket Controller, Flow sense
and vacuum control valve
Pump Control
Central Vacuum PumpsMain /Standby
Vacuum Ring Main
Wall Plate Portable APC
Computer with FMS Software
Remote APC in Enclosure
WiFi capable
83Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
System Overview –Integrated Pumps
230VAC
Remote APC with integrated pump
Host PC
Host RS485, ethernet
Ceiling void
Clean room
24VDC 6A PSU
24VDC 1 A PSU24VDC
6A PSU
R2315
Computer with FMS Software
Portable APC
WiFi capable
84Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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NetworkingEthernet
QA Network Client View Node
Engineering Network Client View Node
Connected via Local Ethernet or company wide Intranet services
FMS System Server Node
Prep area Vial cappingFilling
Address 1 Address 2 Address 3
Address 0 Address 0 Address 0
Smart Sockets
Production Area
85Market Leader in TOC AnalysisANATEL
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Maintaining Compliance• Early detection of out of compliance
• Walking window technique
36 rolling samples
0
Newest results per cubic foot
Previous results per cubic foot
0 1 10 0 0 0 0 0 0 00 0
Sum over last 36 samples is 2 ALARM raised for 5.0 µm
particle counts
xx x x
86Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Software
Software is designed to be compliant with GAMP,
Title 21CFR Part 11 and EU-GMP Annex 1
87Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Human Machine Interface
Plan views of Facilities animated to show alarm conditons from Autocad files.
Password Access to all panels and system functions ensure security
Menu screens can be configured in local language
88Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Real Time Trending
Trends provide multiple traces, multiple Y axes, real time and historic switching with alarm limits
Cursor provides analysis features to read actual point values, min,max etc
89Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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Historic Trending
Calendar date entry enables user to select start and stop date required
Cursor allows trace values to be read, traces and alarm levels may be switched on/off. Up to six signature boxes for “sign off”.
90Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Alarm HandlingAlarms can be manually or automatically acknowledged and are time and date stamped on generation, acknowledgement and clearingdown.
91Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Alarm Reconciliation
Alarm reconciliation provides users with detailed information concerningalarm transitions and “in compliance” and “out of compliance” operation
92Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
MET ONE 6000/7000 Series
• Designed to meet ISO 21501 requirements.
• Built for sterile processing environments with VHP-resistant optics, automatic flow control valve and NEMA-rate enclosure (7000)
• Built-in user notification of measurement alarms, flow problems, and sensor condition
• Multiple communication and mechanical installation options
• External alarm and environmental sensor capabilities reduce monitoring system complexity and costs
• Built-in memory and Hach OPC Server provide complete data security during network/computer problems
Featuring Long Life Laser™ technology
93Market Leader in TOC AnalysisANATEL
HIACMET ONE
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Introduction to MET ONE 6000 Series
• 0.2 µm minimum sensitivity• Long Life Laser™• Models 6002, 6003, 6015• Standard 2 channel, optional 4 channel• Built-in flow sensor option.• Multiple I/O option• Remote status indicator light option• RH-Temp probe option
Service port for instrument set-upAlso used for remote indicator light stack
Relative Humidity-Temperature probe connection
Detail diagnostics by status indicator LED
Multi-color status indicator LED
94Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Introduction to MET ONE 6000 Series
– Improved Sensitivity
– Flexible Communications
– Multiple Installation Options
– Enhanced Instrument Diagnostics
– Long Life Laser™ Diode
– Worldwide service and support
95Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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 μm– 0.5 to 10.0 μm
• 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)
96Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
5-Pin Phoenix connector and RJ-45• Ethernet I/O
10-Pin Phoenix connector • Pulse, Serial RS232• Serial RS485 Modbus (RTU or FX)• Analog
97Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Installation Options - Connections
• Reduces re-installation time during routine calibration and maintenance with DIP switch option
• Easy Installation with multiple connection options– Side vacuum connection– Bottom vacuum connection
Bottom vacuum connection
Optional side vacuum connection
DIP switch for RS485 instrument address setting
Makes installation and removal easier
98Market Leader in TOC AnalysisANATEL
HIACMET ONE
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Installation Options - Mounting
Utility Terminal Box Mounting Option
Wall Plate Mounting Option
DIN Rail (Standard) Mounting Option
Various mounting options offer shorter installation and removal time
99Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
MET ONE 7000 Series
100Market Leader in TOC AnalysisANATEL
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Introduction to MET ONE 7000 Series
Service port for instrument set-upAlso can be used for optional
remote display unit (future enhancement)
Optional Relative Humidity-Temperature
probe connection
Optional remote indicator light port
Multi-color status indicator LED
• ISO 21501 compliant design
• Multiple I/O option
• Built-in enhanced instrument status and user notification indicator
• Long Life Laser™
• VHP tolerant flow path and optics
• Wall plate, umbilical cords and tubes with quick connect fittings for ease of installation and removal
• Up to 1000 sampling data storage
• 0.3 µm sensitivity, 0.1 or 1.0 cfm flow rate
• Built-in flow sensor option
• Remote status indicator light option Standard 2 channel, optional 4 channel
• Sealed enclosure with sealed connectors
• RH-Temp probe option
• Free set-up utility program
101Market Leader in TOC AnalysisANATEL
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Flexible Communication Options
Save FMS integration costs, repair and inventory related costs with multiple communications
• Serial I/O (RS-485 with Modbus RTU or FX protocol)
• Ethernet
• Analog
• Wireless
RJ 45 sealed connectorfor Ethernet, RS485 serial or
Analog I/O Makes integration to any FMS easier
102Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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
• Reduces re-installation time during routine calibration and maintenance with DIP switch feature for serial units
• Quick-connect type sealed vacuum connection
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
Quick connect type vacuum connector
For ease of installation
103Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Ease of Installation Features • Wall plate for terminating end-user cables
and tubing, reduces disruption to connectivity during routine calibration
• Umbilical with quick connect sealed connectors protect counter from wash down and make reinstallation easy
• Quick-connect type sealed vacuum connection makes reinstallation during routine calibration easy
User terminates wiring, tubing at the rear end of
the wall plateMakes installation easier
Umbilical cords and tubing supplied to
connect the counter with wall plate
For ease of installation and subsequent removal for routine calibration and maintenance. Ensure sealed connections
Wall Plate - FrontMakes installation and
removal of counter easier
104Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Installation Features - Standard Accessories
Item Number
Description
1 MET ONE 7000 Counter
2 Mounting Plate
3, 4 Isokinetic Probe (0.1 or 1.0 cfm)
5 Wall Plate
6 Communication Cable with Sealed RJ-45 Connectors
7 Power Cable AC or DC
8 Vacuum Tubing with Sealed Quick Connectors
• Reduces initial installation time• Minimizes removal and re-installation time during routine calibration and
maintenance• Provides wash-down tolerance with sealed umbilical and tubing
105Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Enhanced Instrument Diagnostics
• Instrument can be diagnosed for flow, sensor, communication failures, and count alarm or count alert through built-in or external light stack
Steady Green = Normal (set by software or internal)
Flashing Red = Count Alarm (set by software or internal)
Flashing Yellow = Count Alert (set by software only)
One short flash, one long flash Blue = Flow Fail (set by software or internal)
Solid Blue = Sensor Fail (set by software or internal)
Flashing Blue (2 Hz) = Communication Failure (internally set based on communication timeout)
• Enhanced diagnostics reduce trouble shooting time and downtime
Built in or optional remote multi-color status
indicator LED
106Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Enhanced Instrument Diagnostics
• Instrument can be diagnosed for flow, sensor, communication failures, and count alarm or count alert through built-in or external light indicator
Steady Green = Normal (set by software or internal)
Flashing Red = Count Alarm (set by software or internal)
Flashing Yellow = Count Alert (set by software only)
One short flash, one long flash Blue = Flow Fail (set by software or internal)
Solid Blue = Sensor Fail (set by software or internal)
Flashing Blue (2 Hz) = Communication Failure (internally set based on communication timeout)
• Enhanced instrument status indication reduce troubleshooting time and downtime
Built in or optional remote multi-color status
indicator LED
107Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Met One 6000/7000 Setup Utility Program
• Reduce set-up time with the Met One 6000/7000 setup utility program – Local Setup– LAN Setup– Data Display
• Reduce trouble shooting time – Run Met One 6000/7000 series remote counters without FMS software– Obtain instrument information such as model, serial number and built in
flow sensor
108Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Local Setup Screen Capture
109Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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LAN Setup Screen Capture
110Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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Data Display Screen Capture
111Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Environmental SensorsMeasurement of Temp/RH, Differential Pressure, Air Flow and Temperature of Fridges, Freezers and Incubators
DifferentialPressureSensor
Temp/RHSensor
Up to 1 km and 1000 channels
112Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Environmental Sensors
DP Panels provide central location for signal connection for Temp/RH, PT100s, 4-20mA, DP tubes and digital I/O ( alarms etc.)
113Market Leader in TOC AnalysisANATEL
HIACMET ONE
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Alarm Indication
• Must provide alarm feedback e.g.
– via “traffic light” stack– via alarm message display– via ‘volt free’ contact to BMS– via network– via pager/SMS text
114Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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
115Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Alarm Message Display
Alarm Indicators and Message Displays can be distributedaround the facility
116Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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Alarm Message Display
Alerts staff within facility that monitored parameters are out of limitsFour line LCD display shows local parameters currently in alarmBuilt - in Sounder announces arrival of new alarm conditionsLocal Mute Button, silences sounder without leaving the room
117Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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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
• Large FMS systems requiring:– more than 10 – 20 sensors, – alarm messaging, – remote client PCs, – custom screens & maps, – consolidated reports, – batch features, etc.
are best supported with custom integrated systems such as Hach UltraVision Online, Pharmagraph enVigil FMS, Wonderware, Intellution, etc
• Hach’s OPC Server enables flexibility for ALL software solutions
118Market Leader in TOC AnalysisANATEL
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Low-cost, Simple enVigil Lite 2for Aseptic Production Monitoring
Ethernet
RS-485
119Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Large, Customized, Batch-Driven UVO Systemsfor Aseptic Production Monitoring
Client # 1Fill Line A
Server/client with database
Fill Line A
Fill Line B
Grade C & D monitoring
Client # 2Fill Line B
Ethernet
RS-485
Ethernet or RS-485
120Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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OPC Server for Aseptic Production
Met One OPC Server
“Translator” that converts data from all Met One sensors into the language of the customers preferred system.
Database
Sensor Control & OPC Server
Crystal Reports
Sensor network
Paper data & PDF files
Sensors controlled via MODBUS / TCP
Data from sensors configured for online operation
Data from sensors configured for offline portable operation
CustomerSoftware
(SCADA, UVO, etc.)
Real-time data & control
Historical electronic data
121Market Leader in TOC AnalysisANATEL
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Pharmaceutical FMS Installations
• Many hundreds since 1987
Every major pharmaceutical company on every continent
122Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Summary
• Review your whole particle monitoring program relative to evolving regulations and standards
• Review the amount of manual, paper-based monitoring
• Use automation as an opportunity to improve compliance while simultaneously gaining efficiency
• Involve all internal “stake holders”
• Work with flexible suppliers using open architectures to enable maximum integration and preserve options for future expansion
123Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Table: Sampling Strategies based on ISO 14644 and EU GMP Annex 1
Grade Classification Regular EM Program Process Monitoring
A
1. Frequency = 6 months2. Minimum number of
sample positions: ISO 14644-1 = SQRT area
3. Minimum sample volume: Annex 1 = 1 cubic meter
1. Frequency = a/r (daily ????)2. a/r; sometimes based on
Minimum number of sample positions: ISO 14644-1 = SQRT area
3. Minimum sample volume: a/r4. best practice: (3) 1-minute
counts
1. Continuous during process
2. Key high risk positions3. No minimum volume
defined
B
1. Frequency = 6 months2. Minimum number of
sample positions: ISO 14644-1 = SQRT area
3. Minimum sample volume: Annex 1 = based on ISO 14644 minimum
4. Min volume (5µm) = 24.36 cubic feet (0.69 m3)
1. Frequency = a/r (daily ????)2. a/r; sometimes based on
Minimum number of sample positions: ISO 14644-1 = SQRT area
3. Minimum sample volume: a/r4. best practice: (3) 1-minute
counts
1. “Frequent” during process; “continuous” may be preferred
2. Key elevated risk positions3. No minimum volume
defined
a/r = as required
124Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
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Table: Sampling Strategies based on ISO 14644 and EU GMP Annex 1
Grade Classification Regular EM Program Process Monitoring
C
1. Frequency = 12 months2. Minimum number of sample positions: ISO 14644-1 = SQRT area3. Minimum sample volume: (5 µm) Annex 1 > ISO 14644-1 = 0.24 cubic foot
1. Frequency = a/r (weekly ????)2. a/r; sometimes based on Minimum number of sample positions: ISO 14644-1 = SQRT area3. Minimum sample volume: a/r4.best practice: (3) 1-minute counts
1. no requirement2. Low risk3. No minimum volume defined
D
1. Frequency = 12 months2. Minimum number of
sample positions: ISO 14644-1 = SQRT area
3. Minimum sample volume: (5 µm) Annex 1 > ISO 14644-1 = 0.024 cubic foot
1. Frequency = a/r (monthly ????)2. a/r; sometimes based on Minimum number of sample positions: ISO 14644-1 = SQRT area3. Minimum sample volume: a/r4.best practice: (3) 1-minute counts
1. no requirement2. Low risk3. No minimum volume
defined
a/r = as required
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Regulations and Guidance for the Manufacture of Sterile Medicinal Products ISO 14644 and EU GMP
Annex 1
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Particle Count Theory and Calibration (ISO 21501)
127Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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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
128Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Optical Particle Sensor Configuration
129Market Leader in TOC AnalysisANATEL
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Global Innovator in Fluid Particle Applications
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Inlet Tube
Laser beam viewed in cross section
The View Volume is The area where the air stream and the
laser beam intersect
Sensor View Volume
Requires:Even illuminationPrecise alignment
130Market Leader in TOC AnalysisANATEL
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The larger the particle, the larger thecorresponding output pulse from the sensor.
Particle Sizing
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Counting Electronics
Digital signals to counting circuitry
Analog Signal in
+V
+V
+V
CH1
CH2
CH3Threshold CircuitThis circuitry is
duplicated from onechannel up to six
channels depending onthe model counter
CH. 1
CH. 3
CH. 2
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Air Particle Counter CalibrationISO 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”
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What is ISO 21501?
• ISO 21501 is a new family of standards describing the instruments and calibration requirements for determining particle size distribution using light interaction methods for both liquid and airborne particle counters.
• ISO 21501 represents the culmination of work by instrumentation manufacturers and industry users and comes at a critical time for the life science industry with the increasing trend for real-time air particle monitoring in cleanrooms using light scattering air particle counters.
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What is ISO 21501 replacing?
Previous calibration methods guidelines:• ASTM F 328-98(2003) “Standard Practice for Calibration of an
Airborne Particle Counter Using Monodisperse Spherical Particles” (withdrawn May 2007).
• IEST-RP-CC014.1 “Calibration and Characterization of Optical Airborne Particle Counters” (providing actual methods to perform the calibration).
• JIS B 9921:1997 - Japanese standard which comprehensively deals with OPC design performance, most notably in the area of counting efficiency.
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ISO 21501 Additional Tests
Before ISO 21501-4• Size calibration
• Size resolution• False count rate
• Sampling time
ISO 21501-4 • Size calibration• Verification of size setting• Counting efficiency• Size resolution• False count rate• Concentration limit• Sampling flow rate• Sampling time• Sampling volume
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ISO 21501 Requirements
Parameter 21501-2LS Liquid
21501-3LE Liquid
21501-4Airborne Comments
Size calibration +/- 2.5% +/- 2.5% +/- 2.5% Standard uncertainty of the mean sizeMedian voltage
Verification of size setting+/- 15%
Cal curve (minimum = 3 points)
+/- 10%Reference material
+/- 10%Cal curve
(minimum = 3 points)Use 10% (As-received)
50% Counting efficiency 50 +/- 30% N/A 50 +/- 20% Close to the minimum detectable size. Concentration < 25% of concentration limit.
100% Counting efficiency100 +/- 30%
1.5 to 3X minimum size
100 +/- 20%Reference material< 2X minimum size
100 +/- 10%1.5 to 2X minimum
sizeUse 1.5 to 2X minimum size
Size resolution 10% 10% 15%
Manufacturer's recommended particle size. Use area under the curve.>1.5XCC sets markers at 5% medium value (counts)
False count rate Particles per liter (minimum size) N/A Particles per cubic
meter (minimum size)Poisson distribution with a 95% confidence limitOn screen calculator
Maximum particle concentration
Particles per cubic centimeter
Particles per cubic centimeter
Particles per cubic meter (minimum size)
10% Coincidence loss (calculated)On screen calculator
Sample flow rate MFR standard uncertainty
MFR standard uncertainty +/- 5%
Volumetric flow rateIf unit has flow rate control systemInclude flow rate uncertainty (all)
Sample time +/- 1% +/- 1% +/- 1% On screen calculatorSample volume +/- 5% +/- 5% N/A On screen calculator
Response rate N/A N/A 0.5%10 min at concentration limit (minimum size), Sample (<60 sec) then filter (10 sec), then sample (< 60 sec)
ISO 21501 Requirements
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Calibrating Air Counters with PSL Spheres
Mean size
Std Deviation
f
size
NIST-traceable standard particles have normal distribution
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Particle Count Distribution
millivolts (Particle “Size”)
Num
ber o
f Par
ticle
s
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Resolution/Counting Efficiency (Accuracy)
N
Particle size
0.3 µm 0.5 µm
Good resolution showing separation of channels
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Resolution/Counting Efficiency (Accuracy)
N
Particle size
0.3 µm 0.5 µm
Poor resolution leads to poor counting accuracy: • “undercounting” in smaller sized channels
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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%
Counting efficiency must be 50% ±20%
AND
Channel 1
Counting efficiency must be 100% ±10%
Using PSL that is 1.5 – 2 times the minimum specified size
Counting Efficiency – ISO 21501
At the counter minimum specified size
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Ideal: Even illumination in the view volume provides the same pulse height regardless of where the particle passes through the beam
=Laser beam in cross section
Particle
Illumination Uniformity Affects Resolution
=
=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
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The amplitude of the sensor output is a function of the particle’s residence time in the view volume.
50 lpm flow rateAs flow rate is increased, residence time decreases and response decreases
100 lpm flow rate
At very high flow rates, performance can be challenging as the particles pass through the view volume very quickly and calibration is based on a weaker signal
28.3 lpm flow rateAt 28.3 LPM, residence time yieldsa strong response from 0.5µ particle
Effects of Flow Rate on Pulse Height
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Sensor View Volume Optics and Flow
Small inlet/outlet Nozzle• Good optical uniformity• Low flow turbulence
Large inlet/outlet Nozzle• Poor optical uniformity• Higher flow turbulence
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Design ConsiderationsPump Type Image Advantages Disadvantages
Roots(Hach Met One Patent)
High flowLow powerLightweightBest vacuum
Blower High flowLow powerLightweight
Poor vacuum(requires larger inlet nozzle)
Carbon Vane High flow High powerHeavyweightMaintenance
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Hach Ultra and ISO 21501 Designed Compliant Instruments:
MET ONE 3400 Series
MET ONE 6000 SeriesMET ONE 7000 Series
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HACH Calibration Software Core Cal 3
• Ability to provide a premium ISO 21501 calibration to the customer resulting in increased service opportunity.
• Same procedures & software for all HACH distributors Equivalent to a Factory calibration
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Core Cal 3 Features Continued
• Automatic counter detection• Real-time graphing capability
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Professional Documentation• Professional Abobe™ PDF certificates• Custom logo capable• Incorporated into Hach calibration procedures
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Competitor’s 100 lpm PHA Curve (0.5 um)
• Poor optical performance leads to very poor resolution
• Poor signal-to-noise leads to poor differentiation between noise and real particle counts
This particle counter does not meet the JIS 9921 or ISO 21501 standard for counting efficiency
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Ultra High Flow Considerations (100 lpm)
• Impact on immediate environment and airflow patterns in critical areas– Isokinetic probe must be matched to particle counter flow rate– High exhaust rate of sampled air may disturb room air flow
• Disturbance of airflow patterns in restricted areas due to high rate of sampled air
– Modest air supply of most LAF cabinets may not be sufficient to support high flow rates without substantial disturbance
– Recommend smoke studies to evaluate potential disturbance of controlled air flow
• Accuracy of size resolution and counting efficiency– Pulsations in high flow pumps cause inconsistent air flow within the counter
resulting in poor size resolution performance – Long term performance – higher maintenance requirements
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Sampling Probes and Mounting High-Flow Unidirectional air bathing
the exposed product during manufacturing
Air from outsideGrade A zone
REMEMBER: There is no
requirement to sample 1m3 of air when monitoring
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Effect of Exhaust Air:Issues in using High-Flow
REMEMBER: There is no
requirement to sample 1m3 of air when monitoring
No exhaust air flow
Exhaust air flow creates turbulence and worse…
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Met One 3400 Roots Pump Operating at 100 lpm (0.5 μm)
• Clearly identified peak, excellent resolution • Exceeds ISO21501 calibration standard
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ISO 21501 Calibration Standard
• Improved compliance– Removes ambiguity by providing a single internationally recognized standard
method for calibration– Harmonization between ISO and GMP guidance
• Improved unit-to-unit reproducibility– All particle counters are referenced to a “gold” standard
• Improved counting accuracy– Reduces false alarms in Grade A areas
All current Met One particle counters from Hach may be calibrated using ISO 21501 at your facility
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MET ONE Portfolio
157Market Leader in TOC AnalysisANATEL
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Total Organic Carbon
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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
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TOC increase and Biofilm
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Correlation between endotoxines and TOC
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On-line vs. conventional lab testing
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Anatel – Theory
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Attribute USP <643> EP 2.2.44
Technology to be used
“… share the objective of completely oxidizing the organic molecules in an aliquot of sample water to carbon dioxide…”
“… have in common the objective of completely oxidising the organic molecules in the sample water to produce carbon dioxide…”
Apparatus “…on-line or off-line… using a calibrated instrument
Use a calibrated instrument on-line or off-line…”
“…has demonstrated acceptable system suitability…”
“…shown to have acceptable system suitability.”
USP <643> & EP 2.2.44 Requirements
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Attribute USP <643> EP 2.2.44
Limit of detection “…0.05 mg of carbon per liter…” “…0.05 mg of carbon per litre…”
Blank and water (rw)
TOC Water“…high purity water as defined under <661> containers…” (conductivity measured just prior to dispensing, of not more than 0.15 µS/cm)“…TOC level of not more than 0.25 mg per liter…”
Reagent Water“…not greater than 1.0 µS.cm-1.”
“…not greater than 0.1 mg/l.”
USP <643> & EP 2.2.44 Requirements
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Attribute USP <643> EP 2.2.44
System Suitability frequency
“…periodically demonstrated…” “…at suitable intervals…”
Standard Solution (rs)
USP Sucrose Reagent grade sucrose
System Suitability Solution (rss)
USP 1,4-benzoquinone Reagent grade 1,4-benzoquinone
Response Efficiency
RE = 100[(rss – rw)/(rs – rw] “not less than 85% and not more than 115%…”System suitability SOPs should include error trapping for systematic errors.
RE = 100[(rss – rw)/(rs – rw] “not less than 85% and not more than 115%…”System suitability SOPs should include error trapping for systematic errors.
Limit response rs –rw limit response (not necessarily 500 ppb)
rs –rw limit response (not necessarily 500 ppb)
USP <643> & EP 2.2.44 Requirements
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Attribute USP <643> EP 2.2.44
On-line locations “…reflect the quality of the water used.” (changed from earlier draft specifying “…quality of the water at the use points…”)
‘…representative of the water used.”
USP <643> & EP 2.2.44 Requirements
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Anatel – Theory
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Anatel Theory of Operation
• The organic compounds in each sample are completely oxidized to CO2 in the presence of UV light and a TiO2 catalyst
• Conductivity of the water sample is measured before and after oxidation
• The difference in conductivity is due to the conductive species produced from the dissolved CO2 in water, and is the basis for calculating the amount of organic carbon in the sample
• The end point of the oxidation process is determined precisely and dynamically by a sophisticated set of algorithms
• Inorganic species that contribute conductivity are constant, and are compensated for in the background measurement
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Principle of operation
Time
Con
duct
ivity
UV on
δ conductivity
Organics oxidized to CO2
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Product Portfolio Positioning
Pharmaceuticals Electronics
A643a
A1000
A1000XP
Anatel TOC
PAT700
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Anatel Performance Criteria
• Low detection limit of 1.0 ppb• TOC and conductivity in a single sensor• Wide sample temperature range• Complete, rapid oxidation• Multiple sensor network for data acquisition and control• Analog, digital and serial data outputs• Convenient system suitability• Multi-point user calibration• Easy validation check• Confirm conductivity meter accuracy and cell constant• Measure grab samples (for model A643 & PAT700)
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A643 overview
• On Line TOC analyzer
• Available in 2 versions (Portable or Stationary)
• Calibration, Suitability & Validation tests pre-programmed on the transmetter
• Completed oxydation of the sample
• Grab sample feature
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PAT 700
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Process piping
Isolation valve
Drain
Using On-line TOC analyzers to Meet USP <643> TOC and <645> Conductivity
Cell Constant can be verified without removing from the line Water system does not have to be re-sanitized
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PAT 700 – Key features - Video
• On-line TOC analysis with complete sample oxidation
• Science-based, risk managing instrument designed to meet all requirements of USP, EP and JP
• OASISTM Onboard, Automated Standards Introduction System
• Integral color touch screen display
• Multiple inputs/outputs including separate analogs for TOC, temperature and conductivity
• Dual UV lamps with UV Detect™ technology for improved reliability and diagnostics
• IP 56 stainless-steel enclosure improves protection from water and particulates
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PAT700 TOC Analyzer with OASISTM
• Onboard, Automated Standards Introduction System
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PAT700 TOC Analyzer with OASISTM
•Reduces operator intervention inserting/changing out bottles and entering data
All bottles for a test installed at once and used in sequence
-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 )
-Information can be written to the bottle by the analyzerAnalyzer tracks amount of standard used and number of reps Voids bottle following test - avoids reuse of bottlesSensor serial number on excursion bottles
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OASISTM Technology - RFID
RFID - Radio Frequency IdentificationStore all information concerning standards
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Bottle Mode – Excursion Mode
• Empty sample bottle with RFID tag can be loaded for excursion sampling
• Analyzer automatically fills bottle with sample from water system under
– User configured TOC value– USP conductivity– 35 or 36 error conditions– Manually
• Information on sample programmed to RFID tag on the bottle– Date, time, serial number, previous TOC, previous conductivity and previous temperature
• Validation bottle can be run automatically to verify analyzer– Selection of excursion with or without validation sample
• Reinforces PAT capability through process analysis and validation
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UV DetectTM Diagnostics
• Direct measurement of UV source performance– Diagnosis of UV when TOC readings
are skeptical– Fast, real-time lamp feedback
On-line: Verified after every TOC analysisOff-line: Can be conducted in diagnostic
mode after lamp replacement
• Provides confidence for on-line water release– Can be used for rouge monitoring– Supports PAT initiative through reduced risk
• More reliable than firmware or simple “hours-of-operation” counters
• Reduces cost-of-ownership
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Integral Color touch screen
• Integral color touch screen display for ease of use and access to information, configuration and analyzer operation
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PAT700 – Portable or Stationary• Optional handle sold separately• Customer installed• Recommended to be used with quick
connect version of analyzer
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“reflect the quality of the water used”
Water treatment
plant
WFItreatment
plant
PurifiedWaterTank
WFITank
PointsOfUse
PointsOfUse
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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.
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Cleaning in Place ValidationTOC & 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
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187Market Leader in TOC AnalysisANATEL
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Cleaning in Place ValidationTOC & Conductivity
• Pre-rinse 1 & 2 : Low or ambient temperature. Aim is to remove majority of product residues.
• Wash 1: Use detergent (sodium hydroxide based). Aim is to clean the vessel. Increase of temperature in order to boos this process
• Post Rinse 1: Aim is to remove caustic residues• Wash 2: Use detergent (citric acid). Aim is to remove caustic
residues• Post rinse 2: Aim is to remove acidic residues. High temperature• Final Rinse: Ambient temperature, for accurate measurement.
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Cleaning in Place ValidationTOC & Conductivity
Time
Con
duct
ivity
Final Rinse
TOC
Start TOC measureStop CIP
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Lab move to online TOC
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Total Organic Carbon
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Liquid Particle Counting
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Effects of Particulate Contamination
• Focus has been on injectable liquids– Possibility to occlude (block) capillaries and
arteries• Red Blood cells are about 5 µm• Capillary (5 to 10 µm) • Large veins (10 to 50 µm)
– Threat of microbial infection
– Possibility of reaction toforeign substances
(RES/allergic reaction)
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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
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Volume Definitions: SVI, LVI
• SVI ex., Antibiotics, Insulin, Cytotoxic drug– Small Volume Injectable– Less than or egal to100 mL– Also known as SVP [Small Volume Parenteral]
• LVI ex., NaCl solution (“IV bag”)– Large Volume Injectable– More than 100 mL– Also known as LVP [Large Volume Parenteral]
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Global Regulations: Particles in Liquids
• USP 32-NF 26 <1> Injections• USP 32-NF 26 <788> Particulate Matter in Injections• USP 32-NF 26 <789> Particulate Matter in Ophthalmic Solutions
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Global Regulations: Particles in Liquids
• EP 6 (6.3) Parenteral Preparations• EP 6 (6.3) - (2.9.19) Particulate Contamination: Sub-visible
Particles
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Harmonization of USP 788 with EP
– Current version USP 32 – May 2009– Current version EP6– <788> Particulate Matter in Injection
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Harmonization of USP 788
• Almost a verbatim copy of EP 2.9.19
• Change in calibration management
• At least (4) sample aliquots to be taken• USP 788 has previously required only (3)
• At least 25 mL pooled sample for SVI<25mL• USP 788 has previously required only 20 mL
• Environment test changed• Test at 10 microns only; no 25 micron limit now• Exactly (5) sample draws of (5) mL• At 10 microns, must be no more than 25 particles in 25 mL
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Comparison of Compendial Requirements for Liquid Particles in Injections
Feature USP 31-NF 26
(USP30
- 33(2) IRA)
EP JP/KP
Number of samples
4 4 3
Size of aliquot or portion
≥ 5 mL ≥ 5 mL ≥ 5 mL
Discard #1 Yes Yes Yes SVI: 10 um counts
≤ 6000 per container ≤ 6000 per container ≤ 6000 per container
SVI: 25 um counts
≤ 600 per container ≤ 600 per container ≤ 600 per container
LVI: 10 um counts
≤ 25 per mL ≤ 25 per mL ≤ 25 per mL
LVI: 25 um counts
≤ 3 per mL ≤ 3 per mL ≤ 3 per mL
Environment @ 10 um
≤ 25 per 25 mL ≤ 25 per 25 mL ≤ 5 per 10 mL
Environment @ 25 um
No test No test ≤ 2 per 10 mL
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Comparison of Compendial Requirements for Liquid Particles in Injections
Container Type USP 29 <788>
EP 2.9.19
USP 31-NF 26
Volume <25 mL SVI/SVP Table 1 SVI
Test 1.B Test 1.B Counts per container
25 mL <= Volume <100 mL
SVI/SVP Table 1 SVI
Test 1.B Test 1.B Counts per container
Volume = 100 mL SVI/SVP Table 1 SVI
Test 1.B Test 1.B Counts per container
100 mL > Volume LVI/LVP Table 1 LVI
Test 1.A Test 1.A Counts per mL
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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].
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HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Calibration & System Suitability
USP <788> 31 and earlierInstrument Standardization – IST
- Sample Volume accuracy- Sample Flow Rate- Calibration (Moving Windows)- Sensor Resolution- Particle Counting Accuracy – with USP Particle Count RS
Do be performed every 6 months
203Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Calibration & System Suitability
What is the USP Particle Count RS?2 bottles of blank water2 bottles containing 10 and 15µm particles, with a well know 10µm particles concentration and a well know ratio of counts at 10µm to the counts at 15µm
204Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Calibration & System Suitability
205Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Calibration & System Suitability
USP <788> 32Harmonized with EP & JP
- Calibration with Particle Sphere Latex (sizes between 10 and 25µm)
- System Suitability with USP Particle Count RS
No timeframe – commonly every year
206Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Calibration & System Suitability
Hach recommendationCalibration + IST every 6 months (Sample Volume accuracy; Sample Flow Rate; Calibration; Sensor Resolution; Particle Counting Accuracy – USP Particle Count RS)
On a regular basis (1 to 3 months), system suitability with USP Particle Count RS.
207Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne 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
208Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
PharmSpec 2.2 Software
Supports Compendial standards from USP, EP, JP and KP for Injectables and Ophthalmics
209Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
PharmSpec 2.2 Software
Support Standardization tests:-Moving Windows
-Sensor resolution
-Volume Accuracy
-USP Counting accuracy
-Flow rate
-Electronic resolution
210Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
PharmSpec 2.2 Software
Permits users to comply with FDA 21 CFR Part 11 -“Electronic Records, Electronic Signatures”
211Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Update for PharmSpec
http://www.hachultra.com/index.php/hachultra/tools/downloads/pharmspec_2_0_downloads
•Customer can download compendial update at “no charge” from hachultra.com website
212Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
Product Portfolio Positioning
HIAC 9703-
1997
HIAC 8103-
1990
HIAC 9705-
2006
213Market Leader in TOC AnalysisANATEL
HIACMET ONE
Global Innovator in Fluid Particle Applications
Leader in Airborne Particle Counting
9705 Features: Sides
HandlesEasily moved
Sensor CleanoutQuick access for removing blockages
Thermal printerDelivers data immediately
• Counts• Averages• Standard Deviation
Software for computer – PHARMSPECInclude all EP & USP procedure test
User procedure builder
IQ/OQ doc
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