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Particle Counting

-
Theory
-
Guidelines
-
Monitoring

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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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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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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

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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

Medical and photographic films


Contamination prevents complete image recovery

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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

Non-viable particle count monitoring Non-viable particle counting offers


is a critical component of the total potential for real-time response
Environmental Monitoring program
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Relative Sizes of Particulate Matter

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

Table salt Bacteria

Pencil cells
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Particles Found in a Cleanroom

Aluminosilicate

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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

Principle: Light Scattering 11


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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 3400 Series


Cleanroom classification
Environmental monitoring
Short-term online sampling

MET ONE 6000 & 7000 Series


MET ONE HHPC for production monitoring Grade A & B areas
Handheld particle counter
Used for troubleshooting

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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
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Tubing Transport Loss

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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

Manual Sequential Continuous 17


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Cleanroom and Clean Zone Classification
Classification 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


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Environmental Monitoring
Determine readiness of room to carry out designated task

Performed whenever relevant activity will occur daily work

Number of sample points defined by risk


Typically performed with assessment
portable counters 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


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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


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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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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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Classification Standards for Airborne Particles

General Air Monitoring Standards

ISO 14644-1
Classification of air cleanliness
ISO 14644-2
Specifications for testing and monitoring to
prove continued compliance with ISO
14644-1
ISO 14644-3
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

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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

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Classification: ISO 14644-1

A sample size with at least 20 theoretical particles, or

Minimum sample volume 2.0 liter

Minimum sample time 1 minute

Minimum number of 1
whichever is
locations greatest
with at least 3 samples
total

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Classification Limits ISO 14644-1

Class Number of Particles per Cubic Meter by Micrometer Size

0.1 m 0.2 m 0.3 m 0.5 m 1 m 5 m

ISO 1 10 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

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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 particles
Volume = X 1000 liters
3520 particles

Volume = 5.7 liters


Greater than 2.0 liters so minimum sample volume is satisfied

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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

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

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Continued Compliance:
ISO 14644-2

Schedule of Tests to Demonstrate Continuing Compliance

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
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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

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Example: ISO 14644-1 Classification

Vial
Washing Lyo 1
Station
1 2 3 4 5 6

Lyo 2

Calculations for Number of Points:


Area of clean zone = 80 m
Take the SQRT (80) = 8.94 9
Lyo 3
Rounding up to next integer = 9 sample positions

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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.

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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.

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Example
ISO 14644-1 Calculations

1. Average sample data values at each position


2. Normalize the average to number of particles per cubic meter
3. Compare normalized value to the target class limit; normalized value
at each and every sample point must be less than 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 deviation
b) Use Students T-factor from tables
c) Calculate UCL
d) Compare to classification limit; UCL must
not exceed the applicable limit

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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

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Probable Revisions to
ISO 14644-1, -2

2. Eliminate Students 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

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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.

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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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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.

5. Indicate that single digit limits for ISO Class 1 and 2


create challenges to timely execution

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

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 rigid


than FDA cGMP Guidance
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EU GMP Annex 1 - 2003

Emphasizes continuous monitoring for Grade


From EU Annex 1 A and recommends for Grade B areas
The guidance has A continuous measurement system should be
been reviewed in the used for monitoring the concentration of
light of the particles in the Grade A zone, and is
international standard recommended for the surrounding Grade B
EN/ISO 14644-1 and areas.
amended in the
interests of
harmonisation but Introduces concept of measuring one cubic
taking into account
specific concerns
meter for routine testing (Meaning: classification,
unique to the not in-process monitoring)
production of sterile
medicinal products.

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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

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
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EU GMP Annex 1 Revised:
1 March 2009
Limits at 5 microns for Grade A
1 per cubic meter 20 per cubic meter

At Rest
At Rest In Operation

Grade Maximum permitted number of particles/m3 equal to or above


0.5 m 5 m 0.5 m 5 m
A 520
3 500 20
1 520
3 500 20
1
B 520
3 500 29
1 352 000
350 900
2 000
C 352 000
350 900
2 000 520 000
3 500 29 000
20
D 335000
520 000
000 29 000
20 not defined not defined

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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

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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

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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

Better area/location management


13

Freeze
14 Dryer 3

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

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Intuitive User Interface!

Better area/location management

3400 # 1 3400 # 2 3400 # 3

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Intuitive User Interface!
Location #1
Location #2

Group = Sampling Recipe Area #1


Location #4
Group is a collection of Location #3
pre-set sampling
parameters and alarm
limits
Individual
Location setting

Better group management


Location #N

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.

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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

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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

Meets ISO 21501-4


Resolution
Sensitivity

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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

53
Market Leader in
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MET ONE Particle Counting
Met One 3445 revised 3400 Datasheet

54
Market Leader in
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MET ONE Particle Counting
Met One 3445 revised 3400 Datasheet

55
Market Leader in
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MET ONE Particle Counting
Met One 3445 - Specifications

56
Market Leader in
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MET ONE 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

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

Satisfy Corporate standards


Length of User Name
Length of Password

Audit Trail of User actions

58
Market Leader in
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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

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

59
Market Leader in
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PortAll 2.4 Whats new

Support for USB Memory Stick transfer


Binary format cannot be edited

Only recent Raptor versions of 3400

60
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PortAll 2.4 Whats new

Crystal Reports engine


Standard reports
Custom by user
Custom by Systems Group
New! EU GMP Annex 1 report

61
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MET ONE Particle Counting
PortAll 2.4 Whats new
Compliance reports stored
in a locked PDF format

Suitable for archive in


LIMS or other data
management system

Fully supports 21 CFR 11

62
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MET ONE Particle Counting
PortAll 2.4 New Data Sheet

63
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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

64
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MET ONE Particle Counting
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.

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.
Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009
65
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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

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 !!!

Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009

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

Where vials are filled (2,3)


Surrounding Grade B background (4)
Where the vials are partially stoppered (5) Lyo 3
Loading area in front of lyophilizers must be Grade A if
product is not fully stoppered (6,7)

68
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Use Monitoring System for Classification

Reduce the number of


manually monitored
classification points

SAVE TIME!

Add a wireless portable for room


classification
69
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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

70
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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


Less than 1 foot
operators (12 inches or 30 cm)
Examples:
Descrambler table
Filling needles
Stoppering process

71
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MET ONE Particle Counting
Sampling Probes and Mounting
Unidirectional air bathing
the exposed product during
manufacturing

Isokinetic sample probe


for particle monitoring
Exposed product or
(not positioned directly
over exposed product) vials/ampoules

72
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Where to Monitor?

73
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Positioning the Probes
Turntable

Probe shown with Cap in


place

74
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MET ONE Particle Counting
Positioning the
Probes Filling Line

<305mm

75
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MET ONE Particle Counting
Positioning the Probes
Stoppering Station

<305mm

76
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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.

Note: Revision of EU Annex 1 2003 completed, effective date of 01 March 2009

77
Market Leader in
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Interference from Product
(Powder Filling)

Unidirectional air bathing the


exposed product during
manufacturing

Higher sample probe


for monitoring during
production

Exposed product or
vials/ampoules

Sample probe to
demonstrate air
quality before filling
process

78
Market Leader in
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MET ONE Particle Counting
Recommendations
Powder Fill Line

Inlet HEPA Filter

Outfeed
from
tunnel

= Position of monitoring during filling


= Positions of monitoring at rest
79
Market Leader in
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MET ONE 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

80
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System Overview
Multiple Pumps
230VAC

Host RS485, ethernet

Pump Controller Pump Controller


With Flow sensor With Flow sensor

24Vdc
PSU
Vacuum Pump Vacuum Pump
Ceiling void

Computer with Clean room


FMS Software
Wall Plate
Portable APC

Remote APC
in Enclosure

WiFi capable 81
Market Leader in
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System Overview
Central Vacuum
24 VDC Vacuum Ring Main
Pump
Control
Host RS485,
ethernet

Smart Socket Smart Socket


Host PC Controller, Flow sense Controller, Flow sense
and vacuum control and vacuum control
valve valve Central
Vacuum Pumps
Main /Standby
Plant room

Computer with Clean room


FMS Software

Wall Plate Portable APC

Remote APC in
Enclosure
WiFi capable
82
Market Leader in
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MET ONE Particle Counting
System Overview
230VAC
Integrated Pumps

Host RS485, ethernet

Host PC

24VDC
24VDC 24VDC 1 A PSU
6A PSU 6A PSU
Ceiling void

Computer with Clean room


FMS Software
R2315 Portable APC

Remote APC with


integrated pump WiFi capable
83
Market Leader in
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MET ONE Particle Counting
Networking
Ethernet

FMS System Server Node

QA Network Client View Node

Production Area
Prep area Filling Vial capping

Address 0 Address 0 Address 0

Engineering Network Client View Node

Address 1 Address 2 Address 3 Connected via Local Ethernet or


company wide Intranet services
Smart Sockets

84
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MET ONE Particle Counting
Maintaining Compliance
Early detection of out of compliance
Walking window technique

Newest results per cubic foot

Previous results per cubic foot

x x 0 0 0 0 0 0 0 0 0 0 0 1 0 1 x x

Sum over last 36


samples is 2 ALARM raised for 5.0 m
particle counts

36 rolling samples
85
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Software

Software is designed to be compliant with GAMP,


Title 21CFR Part 11 and EU-GMP Annex 1

86
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MET ONE 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

87
Market Leader in
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MET ONE Particle Counting
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
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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
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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
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Leader in Airborne
MET ONE Particle Counting
Alarm Reconciliation

Alarm reconciliation provides users with detailed information concerning


alarm transitions and in compliance and out of compliance operation 91
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MET ONE 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 Featuring Long Life Laser technology
complete data security during network/computer
problems

92
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MET ONE Particle Counting
Introduction to MET ONE 6000 Series

Multi-color status
indicator LED

Detail diagnostics by 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

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
93
Market Leader in
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MET ONE Particle Counting
Introduction to MET ONE 6000 Series

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

5-Pin Phoenix connector and RJ-45 10-Pin Phoenix connector


Ethernet I/O Pulse, Serial RS232
Serial RS485 Modbus (RTU or FX) 96
Market Leader in Analog
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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

DIP switch for RS485


instrument address setting
Makes installation and removal easier

Optional side vacuum


connection

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

DIN Rail (Standard) Mounting Option

Utility Terminal Box Mounting Option

Wall Plate Mounting Option 98


Market Leader in
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MET ONE Particle Counting
MET ONE 7000 Series

99
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MET ONE Particle Counting
Introduction to MET ONE 7000 Series

ISO 21501 compliant design


Multiple I/O option Multi-color status
indicator LED
Built-in enhanced instrument status and user
notification indicator
Long Life Laser
VHP tolerant flow path and optics Optional remote indicator
light port
Wall plate, umbilical cords and tubes with
quick connect fittings for ease of installation
and removal
Up to 1000 sampling data storage
0.3 m sensitivity, 0.1 or 1.0 cfm flow rate
Built-in flow sensor option
Optional Relative Humidity- Service port for instrument set-up
Remote status indicator light option Standard Temperature Also can be used for optional
probe connection remote display unit
2 channel, optional 4 channel (future enhancement)

Sealed enclosure with sealed connectors


RH-Temp probe option
Free set-up utility program 100
Market Leader in
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MET ONE Leader in Airborne
Particle Counting
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 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

Reduces re-installation time during routine


calibration and maintenance with DIP switch feature
for serial units

Quick-connect type sealed vacuum connection

Quick connect type


vacuum connector
For ease of installation

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

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

Umbilical cords and


User terminates wiring, tubing supplied to
tubing at the rear end of connect the counter
the wall plate with wall plate
Makes installation easier For ease of installation and
subsequent removal for routine
calibration and maintenance.
Ensure sealed connections
103
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MET ONE Particle Counting
Installation Features - Standard
Accessories
Reduces initial installation time
Minimizes removal and re-installation time during routine calibration and
maintenance
Provides wash-down tolerance with sealed umbilical and tubing
Item Description
Number

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

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

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)
105
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Leader in Airborne
MET ONE Particle Counting
Enhanced Instrument Diagnostics
Built in or optional remote
multi-color status
Enhanced instrument status indication indicator LED

reduce troubleshooting time and downtime

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)
106
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MET ONE 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

107
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Local Setup Screen Capture

108
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MET ONE Particle Counting
LAN Setup Screen Capture

109
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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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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE Particle Counting
Environmental Sensors
Measurement of Temp/RH, Differential Pressure, Air Flow
and Temperature of Fridges, Freezers and Incubators

Up to 1 km and 1000 channels

Differential
Pressure
Sensor

Temp/RH
Sensor

111
Market Leader in
ANATEL TOC Analysis
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HIAC Fluid Particle Applications
Leader in Airborne
MET ONE 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.)

112
Market Leader in
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HIAC Fluid Particle Applications
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MET ONE Particle Counting
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

113
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HIAC Fluid Particle Applications
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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
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MET ONE Particle Counting
Alarm Message Display

Alarm Indicators and Message Displays can be distributed


around the facility 115
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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
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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

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

Hachs OPC Server enables flexibility for ALL software solutions

117
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Low-cost, Simple enVigil Lite 2
for Aseptic Production Monitoring

Ethernet
RS-485

118
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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

Ethernet or RS-485 Grade C & D


monitoring

Fill Line
B
119
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MET ONE Particle Counting
OPC Server for Aseptic Production

Met One OPC Server

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

Translator that converts data from all Met One sensors


into the language of the customers preferred system. 120
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Pharmaceutical FMS Installations

Many hundreds since 1987

Every major pharmaceutical company on every continent 121


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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

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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

1. Frequency = 6 months 1. Frequency = a/r (daily ????) 1. Frequent during process;


2. Minimum number of 2. a/r; sometimes based on continuous may be
sample positions: ISO Minimum number of sample preferred
14644-1 = SQRT area positions: ISO 14644-1 = SQRT 2. Key elevated risk positions
3. Minimum sample volume: area 3. No minimum volume
Annex 1 = based on ISO 3. Minimum sample volume: a/r defined
14644 minimum 4. best practice: (3) 1-minute
B 4. Min volume (5m) = 24.36 counts
cubic feet (0.69 m3)

a/r = as required

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Table: Sampling Strategies based on
ISO 14644 and EU GMP Annex 1
Grade Classification Regular EM Program Process Monitoring

1. Frequency = 12 months 1. Frequency = a/r (weekly ????) 1. no requirement


2. Minimum number of 2. a/r; sometimes based on 2. Low risk
sample positions: ISO 14644- Minimum number of sample 3. No minimum volume defined
1 = SQRT area positions: ISO 14644-1 = SQRT
3. Minimum sample volume: area
(5 m) Annex 1 > ISO 14644- 3. Minimum sample volume: a/r
C 1 = 0.24 cubic foot 4.best practice: (3) 1-minute counts

1. Frequency = 12 months 1. Frequency = a/r (monthly ????) 1. no requirement


2. Minimum number of 2. a/r; sometimes based on 2. Low risk
sample positions: ISO Minimum number of sample 3. No minimum volume
14644-1 = SQRT area positions: ISO 14644-1 = SQRT defined
3. Minimum sample area
volume: (5 m) Annex 1 3. Minimum sample volume: a/r
D > ISO 14644-1 = 0.024 4.best practice: (3) 1-minute counts
cubic foot

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)

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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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Optical Particle Sensor Configuration

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Sensor View Volume
The View Volume is
The area where the
air stream and the
Inlet Tube laser beam intersect

Laser beam viewed in


cross section

Requires:
Even illumination
Precise alignment
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Particle Sizing

The larger the particle, the larger the


corresponding output pulse from the sensor.

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Counting Electronics

+V

Threshold Circuit CH3


This circuitry is
duplicated from one
channel up to six
channels depending on +V
the model counter
Digital signals to
counting circuitry
CH2

Analog Signal in

+V

CH. 3

CH. 2 CH1
CH. 1

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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?

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.

133
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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 ISO 21501-4


Size calibration Size calibration
Verification of size setting
Size resolution Counting efficiency
False count rate Size resolution
False count rate
Concentration limit
Sampling time
Sampling flow rate
Sampling time
Sampling volume 135
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ISO 21501 Requirements
ISO 21501 Requirements
21501-2 21501-3 21501-4
Parameter Comments
LS Liquid LE Liquid Airborne
Standard uncertainty of the mean size
Size calibration +/- 2.5% +/- 2.5% +/- 2.5%
Median voltage
+/- 15% +/- 10%
+/- 10%
Verification of size setting Cal curve Cal curve Use 10% (As-received)
Reference material
(minimum = 3 points) (minimum = 3 points)
Close to the minimum detectable size.
50% Counting efficiency 50 +/- 30% N/A 50 +/- 20%
Concentration < 25% of concentration limit.
100 +/- 30% 100 +/- 20% 100 +/- 10%
100% Counting efficiency 1.5 to 3X minimum Reference material 1.5 to 2X minimum Use 1.5 to 2X minimum size
size < 2X minimum size size
Manufacturer's recommended particle size.
Use area under the curve.
Size resolution 10% 10% 15%
>1.5X
CC sets markers at 5% medium value (counts)
Particles per liter Particles per cubic Poisson distribution with a 95% confidence limit
False count rate N/A
(minimum size) meter (minimum size) On screen calculator

Maximum particle Particles per cubic Particles per cubic Particles per cubic 10% Coincidence loss (calculated)
concentration centimeter centimeter meter (minimum size) On screen calculator

Volumetric flow rate


MFR standard MFR standard
Sample flow rate +/- 5% If unit has flow rate control system
uncertainty uncertainty
Include flow rate uncertainty (all)
Sample time +/- 1% +/- 1% +/- 1% On screen calculator
Sample volume +/- 5% +/- 5% N/A On screen calculator
10 min at concentration limit (minimum size),
Response rate N/A N/A 0.5% Sample (<60 sec) then filter (10 sec), then
sample (< 60 sec)

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Calibrating Air Counters with
PSL Spheres
f

Mean size

Std Deviation

size
NIST-traceable standard particles
have normal distribution
137
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Particle Count Distribution

Number of Particles

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Resolution/Counting Efficiency (Accuracy)

Particle size

0.3 m 0.5 m

Good resolution showing separation of channels 139


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Resolution/Counting Efficiency (Accuracy)

Particle size

0.3 m 0.5 m
Poor resolution leads to poor counting accuracy:
undercounting in smaller sized channels 140
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Counting Efficiency ISO 21501
At the counter minimum Using PSL that is 1.5 2 times
specified size the minimum specified size

Counting efficiency Counting efficiency


must be 50% 20% must be 100% 10%

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
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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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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.

At 28.3 LPM, residence time yields


28.3 lpm flow rate
a strong response from 0.5 particle

As flow rate is increased,


50 lpm flow rate
residence time decreases and
response decreases

At very high flow rates,


performance can be
challenging as the particles
100 lpm flow rate
pass through the view
volume very quickly and
calibration is based on a
weaker signal 143
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Sensor View Volume
Optics and Flow

Small inlet/outlet Nozzle Large inlet/outlet Nozzle


Good optical uniformity Poor optical uniformity
Low flow turbulence Higher flow turbulence
144
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Design Considerations
Pump Type Image Advantages Disadvantages
Roots High flow
(Hach Met One Patent)
Low power
Lightweight
Best vacuum

Blower High flow Poor vacuum


(requires larger inlet nozzle)
Low power
Lightweight

Carbon Vane High flow High power


Heavyweight
Maintenance

145
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Hach Ultra and ISO 21501 Designed
Compliant Instruments:

MET ONE 3400 Series

MET ONE 6000 Series


MET 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

147
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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

149
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Competitors 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

151
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Sampling Probes and Mounting High-Flow
Unidirectional air bathing
the exposed product during
manufacturing

Air from outside


Grade A zone
REMEMBER:
There is no
requirement to
sample 1m3 of air
when monitoring

152
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Effect of Exhaust Air:
Issues in using High-Flow

No exhaust air flow

REMEMBER:
There is no
requirement to
sample 1m3 of air
when monitoring

Exhaust air flow creates turbulence and worse


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Met One 3400 Roots Pump
Operating at 100 lpm (0.5 m)

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

155
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MET ONE Portfolio

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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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USP <643> & EP 2.2.44
Requirements
Attribute USP <643> EP 2.2.44

Technology to share the objective of have in common the objective of


be used completely oxidizing the organic completely oxidising the organic molecules
molecules in an aliquot of sample in the sample water to produce carbon
water to carbon dioxide dioxide

Apparatus on-line or off-line using a Use a calibrated instrument on-line or off-


calibrated instrument line

has demonstrated acceptable shown to have acceptable system


system suitability suitability.

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USP <643> & EP 2.2.44
Requirements

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 TOC Water Reagent Water


(rw) high purity water as defined not greater than 1.0 S.cm-1.
under <661> containers
(conductivity measured just prior to
dispensing, of not more than 0.15
S/cm)
TOC level of not more than 0.25 not greater than 0.1 mg/l.
mg per liter

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USP <643> & EP 2.2.44 Requirements
Attribute USP <643> EP 2.2.44
System periodically demonstrated at suitable intervals
Suitability
frequency

Standard USP Sucrose Reagent grade sucrose


Solution (rs)

System USP 1,4-benzoquinone Reagent grade 1,4-benzoquinone


Suitability
Solution (rss)

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)
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USP <643> & EP 2.2.44
Requirements

Attribute USP <643> EP 2.2.44

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
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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

Organics oxidized to CO2


Conductivity

conductivity

UV on Time

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Product Portfolio Positioning

Anatel TOC

Pharmaceuticals Electronics

PAT700 A1000XP

A643a

A1000

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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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Using On-line TOC analyzers to Meet USP <643>
TOC and <645> Conductivity
Process piping

Isolation
valve

Cell Constant can be verified without removing


from the line Water system does not have to be
re-sanitized

Drain
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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
OASIS Onboard, Automated Standards Introduction System
TM

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 OASIS
TM

Onboard, Automated Standards Introduction System

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PAT700 TOC Analyzer with OASIS
TM

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 analyzer


Analyzer tracks amount of standard used and number of reps
Voids bottle following test - avoids reuse of bottles
Sensor serial number on excursion bottles

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OASIS Technology - RFID
TM

RFID - Radio Frequency Identification


Store 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 analysis
Off-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

Points
Water Of
Purified
treatment Use
Water
plant
Tank

Points
Of
WFI Use
treatment WFI
plant Tank
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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 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
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186
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Cleaning in Place Validation
TOC & 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.

187
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Cleaning in Place Validation
TOC & Conductivity
Conductivity

TOC
Time
Stop CIP
Final Rinse Start TOC measure

188
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Lab move to online TOC

189
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Total Organic Carbon

190
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Liquid Particle Counting

191
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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 m
Capillary (5 to 10 m)
Large veins (10 to 50 m)

Threat of microbial infection

Possibility of reaction to
foreign substances
(RES/allergic reaction)

192
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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

193
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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]

194
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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

195
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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

196
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Harmonization of USP 788 with EP

Current version USP 32 May 2009


Current version EP6
<788> Particulate Matter in Injection

197
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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

198
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Comparison of Compendial Requirements for Liquid Particles in Injections

Feature USP 31-NF 26 EP JP/KP


(USP30
- 33(2) IRA)
Number of 4 4 3
samples
Size of aliquot 5 mL 5 mL 5 mL
or portion
Discard #1 Yes Yes Yes
SVI: 10 um 6000 per container 6000 per container 6000 per container
counts
SVI: 25 um 600 per container 600 per container 600 per container
counts
LVI: 10 um 25 per mL 25 per mL 25 per mL
counts
LVI: 25 um 3 per mL 3 per mL 3 per mL
counts
Environment 25 per 25 mL 25 per 25 mL 5 per 10 mL
@ 10 um
Environment No test No test 2 per 10 mL
@ 25 um 199
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Comparison of Compendial Requirements for Liquid Particles in Injections

Container Type USP 29 EP USP 31-


<788> 2.9.19 NF 26
Volume <25 mL SVI/SVP Table 1 Test 1.B Test 1.B Counts per
container
SVI
25 mL <= Volume SVI/SVP Table 1 Test 1.B Test 1.B Counts per
container
<100 mL SVI
Volume = 100 mL SVI/SVP Table 1 Test 1.B Test 1.B Counts per
container
SVI
100 mL > Volume LVI/LVP Table 1 Test 1.A Test 1.A Counts per
mL
LVI

200
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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].

201
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Calibration & System Suitability

USP <788> 31 and earlier


Instrument 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

202
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Calibration & System Suitability

What is the USP Particle Count RS?


2 bottles of blank water
2 bottles containing 10 and 15m particles, with
a well know 10m particles concentration and a
well know ratio of counts at 10m to the counts
at 15m

203
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Calibration & System Suitability

204
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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

No timeframe commonly every year

205
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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)

On a regular basis (1 to 3 months), system suitability with USP


Particle Count RS.

206
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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
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PharmSpec 2.2 Software

Supports Compendial standards


from USP, EP, JP and KP for
Injectables and Ophthalmics

208
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PharmSpec 2.2 Software

Support Standardization tests:


-Moving Windows
-Sensor resolution
-Volume Accuracy
-USP Counting accuracy
-Flow rate 209
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HIAC
Global Innovator in
Fluid Particle Applications -Electronic resolution
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PharmSpec 2.2 Software

Permits users
to comply
with FDA 21
CFR Part 11 -
Electronic
Records,
Electronic
Signatures

210
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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

211
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Product Portfolio Positioning

HIAC 8103 HIAC 9703 HIAC 9705


- - -
1990 1997 2006

212
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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
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Liquid Particle Counting

214
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