Particle Counting Theory Guidelines Monitoring -...

1Market Leader in TOC AnalysisANATEL

HIACMET ONE

Global Innovator in Fluid Particle Applications

Leader in Airborne Particle Counting

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

--------• On-line TOC Analyzer • EP&USP Harmonization for Liquid Particle


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Agenda



• 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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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

http://www.google.com/imgres?imgurl=http://lh6.ggpht.com/_ahmprYw6wqo/SWoXQO3jM-I/AAAAAAAAAtQ/bcLkpdHa6oA/%255BUNSET%255D.jpg&imgrefurl=http://thingsaboutcomputer.blogspot.com/2009_01_01_archive.html&h=456&w=500&sz=36&tbnid=RdZBbE0hcc45VM:&tbnh=119&tbnw=130&prev=/images%3Fq%3Dhard%2Bdisk%2Bdrive%2Bimage&usg=__3F3dSDJJd3Je7K6TFt57oR4z55k=&ei=G0kpSu-pLYnEM--ewd8J&sa=X&oi=image_result&resnum=1&ct=image


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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 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


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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


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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


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Table salt

Pencil cells

Bacteria

Relative Sizes of Particles


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Particles Found in a Cleanroom

Aluminosilicate


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Guidance Suggested Monitoring

0123456789

10

Bacterium

2 - 8 µm

0.5 µm

Virus: 0.001 µm

5 µm

“Event” driven

Baseline


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How an airborne particle counter works …

Laser Diode

Detector

Mirror

Particle

Light Trap

Principle: Light Scattering


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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 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


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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


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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


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Tubing Transport Loss


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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


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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


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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


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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


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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





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Classification Standards for Airborne Particles

– ISO 14644-1• Classification of air cleanliness

– ISO 14644-2• Specifications for testing and monitoring to

prove continued compliance with ISO 14644-1

– ISO 14644-3• Guidance on instrumentation to be used

for testing for compliance with ISO 14644-1

General Air Monitoring Standards

ISO 14644

1999


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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


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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

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


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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


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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 particles3520 particlesVolume = X 1000 liters

Volume = 5.7 litersGreater 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

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


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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


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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


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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


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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



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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


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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


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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


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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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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


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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


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Agenda





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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 rigidthan FDA cGMP Guidance


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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.”


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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


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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


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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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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


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Better area/location management

3400 # 1 3400 # 2 3400 # 3


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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


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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


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Met One 3445 – revised 3400 Datasheet


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Met One 3445 - Specifications


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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


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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


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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


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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


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• Crystal Reports engine– Standard reports– Custom by user– Custom by Systems Group

• New! EU GMP Annex 1 report


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• Compliance reports stored in a locked PDF format

• Suitable for archive in LIMS or other data management system

• Fully supports 21 CFR 11


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PortAll 2.4 – New Data Sheet


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Agenda





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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.


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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”



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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” !!!


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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)


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Use Monitoring System for Classification

Add a wireless portable for room classification

Reduce the number of manually monitored classification points

SAVE TIME!


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Agenda





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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)


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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


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Where to Monitor?


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Positioning the Probes Turntable

Probe shown with Cap in place


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Positioning the Probes Filling Line

<305mm


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Positioning the ProbesStoppering Station

<305mm


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Monitoring Powder Fill

Section 9:• “For Grade A zones, particle monitoring should be undertaken for the

full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e. g. live organisms and radiological hazards.

• In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed.



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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


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Recommendations Powder Fill Line

Inlet HEPA Filter

Outfeed from

tunnel

= Position of monitoring during filling = Positions of monitoring ‘at rest’


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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


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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


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System Overview –Central Vacuum

Host PC


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


Remote APC in Enclosure

WiFi capable


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System Overview –Integrated Pumps

230VAC

Remote APC with integrated pump

Host PC


Ceiling void

Clean room

24VDC 6A PSU

24VDC 1 A PSU24VDC

6A PSU

R2315


Portable APC

WiFi capable


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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


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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


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Software

Software is designed to be compliant with GAMP,

Title 21CFR Part 11 and EU-GMP Annex 1


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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


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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


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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”.


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Alarm HandlingAlarms can be manually or automatically acknowledged and are time and date stamped on generation, acknowledgement and clearingdown.


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Alarm Reconciliation

Alarm reconciliation provides users with detailed information concerningalarm transitions and “in compliance” and “out of compliance” operation


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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


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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


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– Improved Sensitivity

– Flexible Communications

– Multiple Installation Options

– Enhanced Instrument Diagnostics

– Long Life Laser™ Diode

– Worldwide service and support


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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)


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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


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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


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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


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MET ONE 7000 Series


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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


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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


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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


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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


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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


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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


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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


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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


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Local Setup Screen Capture


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LAN Setup Screen Capture


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Data Display Screen Capture


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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


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Environmental Sensors

DP Panels provide central location for signal connection for Temp/RH, PT100s, 4-20mA, DP tubes and digital I/O ( alarms etc.)


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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


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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


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Alarm Message Display

Alarm Indicators and Message Displays can be distributedaround the facility


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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


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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


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

Ethernet

RS-485


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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


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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


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Pharmaceutical FMS Installations

• Many hundreds since 1987

Every major pharmaceutical company on every continent


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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

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



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


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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



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)


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Agenda





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Optical Particle Sensor Configuration


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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


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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

http://images.google.com/imgres?imgurl=http://www.jsr.co.jp/jsr_e/pd/images/clintex_img.gif&imgrefurl=http://www.jsr.co.jp/jsr_e/pd/fc_pd.shtml&h=122&w=119&sz=14&hl=en&start=1&tbnid=gJPB8HzMkPWuWM:&tbnh=89&tbnw=87&prev=/images%3Fq%3Dclintex%26gbv%3D2%26svnum%3D10%26hl%3Den


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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


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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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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.”



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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)



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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.”



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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

http://www.hachultra.com/index.php/hachultra/catalogue/anatel/anatel_pat700_toc


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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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• 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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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


Volume = 100 mL SVI/SVP Table 1 SVI


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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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


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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


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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


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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.


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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


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Supports Compendial standards from USP, EP, JP and KP for Injectables and Ophthalmics


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Support Standardization tests:-Moving Windows

-Sensor resolution

-Volume Accuracy

-USP Counting accuracy

-Flow rate

-Electronic resolution


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


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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


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Product Portfolio Positioning

HIAC 9703-

1997

HIAC 8103-

1990

HIAC 9705-

2006


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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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Liquid Particle Counting

Particle Counting Theory Guidelines Monitoring -...

Documents

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