3.slide toc ec (21-sep-2005)

Anthony C. Bevilacqua, Ph.D page Mettler-Toledo ThorntonUSP Presentation May 2002

USP and International Pharmaceutical Water Requirements

A Mettler-Toledo Thornton presentation

Pongphan ChongthamPongphan ChongthamBusiness Area Manager Process Analytics Division MT-TH

+66 2 723 0300

FAQFAQ

•• What is the set point exactly for Conductivity?What is the set point exactly for Conductivity?

•• Why after sampling conductivity is so high?Why after sampling conductivity is so high?

•• When do I have to make the calibration for conductivity?When do I have to make the calibration for conductivity?

•• How can I eliminate conductivity value?How can I eliminate conductivity value?

Conductivity Basics

FAQFAQ

Why we’re measure TOC?

Is that replace bacteria test method by TOC?

Where should we have TOC in the plant?

When we can see the TOC value increasing?

The TOC value limit at 500ppb is it?

How can we trust the TOC performance?

Is TOC request only WFI water?

Do we have any problem to grab the sample to test TOC later?

Where is the right place to put TOC analyzer in the water plant?

I have found high TOC value. How can I do?

My water have very perform conductivity, Why still need TOC to check?

Do I able to use TOC and stop Microbial test and Endotoxin test?

I just make cosmetic and tablet medicine then I will no need for TOC analyzer?

TOC only for WFI?

Event to day USP28, I still follow USP23 without TOC requirement.

TOC Basics

Plant Water Source

Coagulation /Reverse Osmosis/

Demineralizers

Cooling Towers/Boilers

Waste WaterRecycle & Discharge

Downstream Processing

Preparation

Reactions

Waste Water

Process

Water

Preparation

Water Cycle

3 section to multi application !!!3 section to multi application !!!

On-line, Off-line, Lab test

On-line

Lab-test

Off-line

Maintenance

QC, QA

Production

On-line, Off-line, Lab test

On-line

Lab-test

Off-line

Purpose for process safety and productivity optimize- heavy duty require- on-time maintenance- hygienic connection require

Purpose for quality control- highly important on human skill- cross link highly important in house and

end user- not continuous monitoring- sampling method high risk to result

Moveable to different installation point- light weight and durable


Source water character

Ground waters Surface waters

Higher Mineral content

Low organic levels

Higher Hardness levels

Less temperature variation

Lower Mineral content

Higher organic levels

Higher TDS levels

Wide Temperature variations

Seasonal fluctuations*

*May cause certain facilities to switch between ground and surface water supplies

Summarize most of all technique

Summarize most of all technique Typical measurements in a UPW Make-up & Distribution Application

Post Filter 0.2 micron

To Points of use

Feed water

Parameters

Cond/Resist(8-12)

pH(5)

ORP(1)

D.O.(3+)

TOC(1-4)

Pressure(3-9)

Flow(6+)

Total pts: ~25-40

Pretreatment

Heat Exchanger RO Prefilter

2-Pass RO

MB

or

CEDI

Degasifier MB PolisherFinal Filter 0.5 micron

UPW Storage

PumpFinal Filter 0.1

micron

UV Sterilizer

0.1 mic POU filters

Cl2 Inj. Acid Inj.

Caustic Inj.

% Rejection % Recovery


Grain monitoring for DI

Grains = ∫ Flow x TDS dt

Grains - cumulative TDS or ion loadFlow - flowrate entering DI bedTDS - total dissolved solids based on

conductivity entering DI bed

Deionization Capacity MonitoringDICapDICapTMTM TOC and Conductivity are just the sensor…..

SmartSmart

Smart

Smar

t

Pulse Pulse

Or mix n’ match• pH/ORP• 4E Conductivity• Pressure• Tank Level

TOC

Conductivity

Flow

DO

Flow

TOC

Technology today

USP and International Pharmaceutical Water Requirements

A Mettler-Toledo Thornton presentation

Pongphan ChongthamPongphan ChongthamBusiness Area Manager Process Analytics Division MT-TH

+66 2 723 0300

• Founded by Dr. Thornton 1964.• Resistivity/Conductivity, TOC, DO, Temperature, Flow, Pressure,

Tank Level, for all fluids, specializing in High Purity Water and UPW.

• Research on high temp UPW, CO2, TOC, calibration, temperature compensation.

• Advisor to SEMI Water Group.• Active member ASTM, ISPE, SEMI.• Chairman USP Pharmaceutical Water Expert Committee.• Acquired by Mettler Toledo 2001.

Background

• USP and the Pharmaceutical Water Expert Committee• Modern History of Pharmaceutical Water

• “Harmonization” and what it means to you

• Status of Pharmaceutical Waters in the US, EU, and Japan – Bulk waters– Production– Conductivity and TOC– Microbiology, more– Packaged (sterilized) Waters

• Recent and proposed changes to USP, EP, and JP related to Water

Agenda

• Water is the most widely used excipient in Pharmaceutical Manufacturing

• Water systems are a significant part of the quality inspections.

• USP - FDA relationship

Why is Water Important?


• Pharmaceuticals and Biotechnology

• Dental Products

• Cosmetics

• Veterinary products

• Drug dispensing devices

• Pharmacies

• Water System Fabricators

• Labs to support these industries

They all use water!!!

Companies/Products Impacted?

• The USP is the U.S. Pharmacopeia.• It is a private, not-for-profit, non-governmental

organization located in Rockville MD. There are no political or governmental links.

• It is dedicated to the development of quality standards for the benefit of the public health.

What is the USP?

The United States Pharmacopeia promotes the public health by establishing and disseminating officially recognized standards of quality and authoritative information for the use of medicines and health care technologies by health professionals, patients, and consumers.

USP Mission?

• The USP are like legislators. They set standards of quality that pharmaceutical (and other) companies are required to adhere to.

• The FDA is like the police. They enforce these standards by inspections.

• Water systems are a significant part of the quality inspections.

What does this mean?

• ~225 doctors, research scientists, pharmacists, technicians, andadministrative support staff.

– Prepare standards and USP text books– Liason to Expert Committees

• ~500 volunteer members of Expert Committees.– 62 Expert Committees - 1 for Pharmaceutical Waters– The Expert Committees have all decision-making authority now

Who Constitutes the USP?

• EP– Some private, some government– ~25 countries, all must agree– Led by British and Swiss companies

• JP– Small governmental staff– Tend to follow USP

• Other– Canadians follow USP– Asians follow Japan?

You must follow the pharmacopeia of the country you wish to market and sell your products

Global Counterparts?


• The USP publishes a complete book every 2 years with updated revisions biannually.

– Effective Jan 1, 2002, USP 25 is in effect. USP 26 comes out in 2004– Updated supplements 2-3 times/year– Revision proposals every 2 months

• Larger companies have entire departments dedicated to keeping up with the USP guidelines. Startups and smaller companies do not.

• Most water system fabricators do not know about pending changes until they hear about them from us or their client.

What is the “USP” book standards?

• 62 Committees, each with their own “experts”. Replaces the Committee of Revision for 5 year cycle.

• Pharmaceutical Water Expert Committee consists of 6 members (from large and small producers) and staff liason (Frank Barletta).

• Includes FDA input directly and indirectly.

• Members are myself (Chair) and persons from MT-Thornton, Abbott, Aventis, Catalytica, Roche, and the FDA.

• Expertise in various aspects of water production, quality, validation, and measurement.

Pharmaceutical Water Expert Committee

• Members are myself (Chair) and persons from MT-Thornton, Abbott, Aventis, Catalytica, Roche, and the FDA.

• Primary task: oversee all Pharmaceutical Water Issues– Harmonization with JP and EP– Packaged waters– Provide definitions for more types of water

• Elected to lead this group because of our experience in Pharmaceutical Water– high purity water systems– analytical measurements

• Most changes reside in the domain of the the Committee. • Interfaces with PDA, PhRMA (WQC), HIMA, other.

Pharmaceutical Water Expert Committee

• Pharmaceutical Water Monographs– Purified Water (bulk)– Water for Injection (WFI) (bulk)– Sterile Purified Water (packaged)– Sterile WFI (packaged)– Sterile Water for Inhalation– Sterile Water for Irrigation– Bacteriostatic WFI

• Test Chapters– <645> Conductivity– <643> Total Organic Carbon– <71> Sterility– <85> Endotoxins– <791> pH

• General Information– <1231> Water for Pharmaceutical Purposes

TodayTomorrow

Relevant Sections of USP

• Feedwater• USP water• Hot water• Sanitization• Rinsing water• Waste water• Potable water

Conductivity/Resistivity & TOC are used to Monitor All Pharmaceutical Waters . .

• Buffer solutions• Bio-Process fluids• Regeneration acids/bases• Reclamation water

Conductivity/Resistivity & TOC are used to Monitor Other Pharmaceutical Fluids…


• Reverse Osmosis• Deionization/Polishing• Filtration• EDI/CDI• Sanitization/UV irradiation• Ion-exchange regeneration• Distillation• Pure Steam Generation

Conductivity/Resistivity & TOC are used to Monitor Pharmaceutical Water Purification Processes

• 1990 - USP and PhRMA agree that there are better test methods for Pharmaceutical waters.

• 1991 - WQC proposes Conductivity and TOC to replace most existing tests for Purified Water and WFI.

• 1991-1995 - WQC evaluates conductivity and TOC instrumentation.

• 1994 - Thornton involvement begins for conductivity and general water issues.

• Controversial issues–“method of manufacture”–“temperature compensation”–TOC “system suitability” tests.

Last 10 Years of USP and H2O

• Winter 1995 - “Ammonia-chloride” model published.

• November, 1996 - USP 23 supplement 5– Requires <645> Water Conductivity testing for PW and WFI.– <643> TOC an optional test for PW and WFI.

• May, 1998 - USP 23 supplement 8.– pH deleted.– Oxidizable Substances deleted – <643> TOC required.

• USP/PhRMA do NOT change packaged water requirements– Chemistry tests still necessary for sterilized waters


• 1999-2000 - EP changes analytical chemistry test for bulk waters.– EP requires conductivity test. Different methods and limits than USP.– Requires TOC for WFI. Same test as USP.– TOC optional for PW.

• 2001 - EP defines HPW. Permits RO in limited applications• 1999-2000 – USP re-organization to include experts in specific

areas, including water, and provide authority to them. • 2000 - Pharmaceutical Waters Expert Committee elected by USP.• Feb 2002 – USP, EP, and JP agree to begin harmonization of

Pharmaceutical Waters• 2004 EP and USP use the same limitation for Conductivity for

WFI• JP15 will coming soon for conductivity and TOC harmonization


A pharmacopoeial general chapter or other pharmacopoeial document is harmonized when a

pharmaceutical substance or product tested by the procedure yields the same results, and the same

accept/reject decision is reached.

Harmonization JP15 coming soon with TOC and Conductivity


EP (4th Ed.) JP (XIII) USP

1. WFI/bulk + + +

2. WFI/sterilised (containers) + + +

3. HPW bulk + – –

4. PW /bulk + + +

5. PW/containers + – –

6. Water for dialysis (bulk + containers) + – –

7. Bacteriostatic WFI (containers) – – +

8. Sterile water for inhalation (containers) – – +

9. Sterile water for irrigation (containers) – – +

10. Sterile PW/containers – – +

11. Sterile PW/bulk – + –

12. Water (tap, well) – + –

Water Qualities/Types Comparison of Bulk PW Requirements

1 UF alone is not capable of removing inorganic ions, RO is not mentioned for purified water 4 if used in dialysis2 as action limit in production section 5 alternative to TOC3 in production section

EP JP USP1. Production Method All techniques • distillation • ion exchange •UF1

• combination of above techniques• all techniques

2. Source water quality Potable water acc. to national legislation of EP Convention members

JP water specification US-EPA drinking water or EU or Japan

3. Total aerobic count/ml Max 1002 – –4. Conductivity (µS/cm@20°C) Max 4.33 – Max 1.15. TOC [mg/l] Max 0.55 – Max 0.56. Bacterial endotoxins/ml Max 0.25 IU4 – –7. Nitrates [ppm] Max 0.2 Not detectable –8. Heavy metals [ppm] Max 0.1 Not detectable –9. Aluminium4 [ppb] Max 10 – –10. Acidity/alkalinity – Test against colour indicators –11. Chloride – Not detectable –12. Sulfate – Not detectable –13. Nitrite – Not detectable –14. Ammonium [mg/l] – Max 0.5 –15. Oxidisable substances <0.1 ml5 0.02 KMnO4 /100 ml < 0.10 ml 0.02 KMnO4/100 ml –

16. Residue on evaporation – Max 1.0 mg/100 ml –

EP JP USP1. Production Method distillation • distillation

• RO + UF, from PW• distillation• RO

2. Source water quality Potable water acc. to national legislation of EP Convention members

JP water specifications US-EPA drinking water or EU or Japan

3. Total aerobic count Max 10/100ml6 – –4. Conductivity (µS/cm@20°C) Max 1.17 – Max 1.15. TOC [mg/l] Max 0.57 Max 0.58 Max 0.56. Bacterial endotoxins per ml Max 0.25 IU Max 0.25 EU Max 0.25 USP-EU7. Nitrates [ppm] Max 0.2 Not detectable –8. Heavy metals [ppm] Max 0.1 Not detectable –9. Aluminum9 [ppb] Max 10 – –10. Acidity/alkalinity – Test against colour indicators –11. Chloride – Not detectable –12. Sulfate – Not detectable –13. Nitrite – Not detectable –14. Ammonium [mg/l] – Max 0.05 –15. Oxidisable substances – < 0.1 ml 0.02M KMnO4/100 ml –

16. Residue on evaporation – Max 1.0 mg/100 ml –

6 Action limit in production section 8 tested exclusively if produced by RO/UF7 in EP in production section 9 if used in dialysis

Comparison of Bulk WFI Requirements Method of Manufacture Requirements USP27

Latest harmonization EP and USP pharmaceutical 2004

1. Feedwater requirements

2. “Method of Manufacture” requirements

3. Microbiology requirements

4. Endotoxins requirements (WFI only)

5. <645> Conductivity

6. <643> TOC

Bulk Purified Water and WFIWhat requirements shall these waters meet?


• Feed water must meet U.S. EPA Drinking Water Requirements or the equivalent drinking water requirements for the EU or Japan.

• Not all countries from Europe are in the EU.

• USP accepts local requirements for the EU and Japan, but there is no reciprocation.

1.Feed Water Requirements

• USP Purified Water to be produced by Distillation, RO, De-ionization, or equivalent means. Same for EP, JP.

• USP WFI to be produced only by distillation or RO.• EP WFI requires distillation only.• JP WFI permits distillation or RO/UF.• Engineering vs academic argument

– Engineer says “Don’t tell me how to make it, just tell me how good it needs to be!”– Academic says “Distillation is a natural process; RO is not. Distillation is self-

sanitizing; RO is a giant bug condominium”

Distillation for true harmonization!

2. Method of Manufacture Requirements

• EP limits are ACTION LIMITS in Production section– Purified Water…..100 cfu/ml– WFI……………..10 cfu/100ml

• USP limits are recommended in <1231> general chapter– Same limits as EP

• JP limits are enforced in drinking water requirements– Same limits as EP

In practice, this is the most widely audited and monitored attribute of PW and WFI.

3. Microbiology Requirements

• <0.25 EU/mL Endotoxin (USP and JP)

• <0.25 IU/mL Endotoxin (EP)

• Same limits and same tests, different reference standard

4. Endotoxin Requirements (WFI only)

• Prior to November 1996, existing chemistry tests date back to 1840. Chemistry tests are qualitative, subject to bias, and off-line.– Carbon dioxide– Calcium– Ammonia– Chloride– Sulfate

• November, 1991 – Conductivity proposed to replace the chemistry tests.

5. <645> Water Conductivity

...“The existing USP monograph tests for chloride, sulfate, calcium, ammonia, and carbon dioxide were introduced into the USP in 1890 or before and may no longer be appropriate with regard to test methodology. While USP water monograph test methodologies for inorganic ions traditionally have been wet chemical methods, which are inexpensive and require little technical skill to perform, such attributes are offset by the qualitative and subjective nature of the antiquated tests. (...) the WQC of PMA proposes to replace them with a conductivity measurement.”...

Stimuli to the Revision Process , Pharmacopeial Forum Nov./Dec. 1991

TOC H2O pHconductivity

resistivityROion-exchangecfu

WQC/PhRMA Initiative


• Maintain/improve the existing water quality.

• Simplify the testing. Reduce the number of tests.

• Use modern instrumentation. Use existing instrumentation. Conductivity and TOC have been reliable tools in Semiconductor, Power and Pharmaceutical facilities for years.

• Quantify the test results. Pass/Fail, but by how much?

• Improve the reliability of the testing. Take out the operator bias.

• Make allowances for on-line, in-line testing.

Basic Goals of USP Conductivity/TOC Testing

• Set up “Stages” for testing to permit on- and off-line tests.

• Take advantage of on-line conductivity measurements.

• Permit off-line conductivity measurements.

• For off-line tests, allow for innocuous contamination that results from CO2 (HCO3

-, H+).

• Eliminate the arbitrary nature of temperature-compensation.

Test Philosophy

• Conductivity is defined as the ability of a solution toconduct current

• The amount of current flowing is roughly proportionalto the number of ions present in the conducting solution

• Conductivity measurement gives information aboutthe total ionic content of all ions in a solution.

Conductivity is the way to measure resistance that was fix between plate 2 plates

Resistivity is the reverse value of conductivity

Ω = 1 / S

Theory of Conductivity

High Concentration=

Low Resistance=

High Conductivity

Low Concentration=

High Resistance=

Low Conductivity

High number of ION make high current flow

What is meaning of ION ? Oil, Hexane, Urea are ION or not ? NaCl, HCl are ION or not ?


• amount of ions in a solution• type of ions (e.g. Cl-, Na+)• mobility of ion

C is the conductivity of the solution (S/cm)zi is the charge of ion ici is the concentration in equivalents per literλi is the equivalent conductance in Siemens cm2 per mole

All ion give you the conductivity number


Sample Conductivity at 25 °C (µS/cm)

Pure water 0.055Distilled water 0.5Streams 1.0Mains water 50Potable water 1060Sea water 50‘00010% NaOH 355‘00031% HNO3 865‘000


Typical conductivity values under different conditions at 25 Typical conductivity values under different conditions at 25 °°CC


• If a voltage U is connected across two plates (electrodes), placed in a solution containing ions, an electric current l flows between the plates

A

U I

L

Resistance(Ω) = 1

Conductance(S)

Resistivity(Ω.cm) = 1

Conductivity (S/cm)


C = Conductivity [S/cm]G = Conductance [S]L = Distance between electrodes [cm]A = Area of electrode [cm2]

C = G x (L/A)Conductivity


R = Resistivity [Ω.cm]M = Resistance [Ω]L = Distance between electrodes [cm]A = Area of electrode [cm2]

R = M x 1/(L/A) Resistivity

1. Put sensor into unknown solution2. Meter read resistance of solution3. That number convert to conductance then

cross by cell constant4. Compensate with temperature to 25C5. Show conductivity value at display

Conductivity = ( 1 / Resistance ) X ( Cell constant )

Verify or calibrate transmitter very important point to make sure the correct reading (NIST traceable calibrator necessary)

Cell constant provided from electrode manufacturing traceable toASTM method (D-1125) for key into the meter function


As we khow about relation between concentration and conductivity that canmake this technical apply to measure the relate parameter.

TDSConductivity x (factor 0.1...1.0)

SalinityNaCl (Tested table)

Acid base determinationAcid-base (Tested table)

All of those parameter are use conductivity meter technique (covAll of those parameter are use conductivity meter technique (covert to concentration ert to concentration standard table). That means accuracy base on conductivity valuestandard table). That means accuracy base on conductivity value

Some measurement range conductivity no change when conductivity Some measurement range conductivity no change when conductivity changed.changed.


1. In-line, non-temperature-compensated conductivity measurement. Measure temperature and conductivity. Look up conductivity limit for that temperature. If measured uncompensated conductivity is < conductivity limit, then Pass - Done. If not:

2. Lab Test : Equilibrate water sample with atmospheric CO2 : If conductivity < 2.1 µS/cm at 25°C, Pass – Done. If not:

3. Lab Test: Saturate previous sample with KCl : Measure pH. Look up conductivity limit for that pH. If measured conductivity (from Stage 2) is < conductivity limit, Pass – Done. If not:

Fail

3-Stage Test Method (effective November,1996) USP <645> Stage 1 & EP Conductivity Limits


0 0.65 0.8

10 0.915 1.020 1.125 1.330 1.435 1.540 1.745 1.850 1.9

MaximumTemperature Conductivity

(°C) (µS/cm) 55 2.160 2.265 2.470 2.575 2.780 2.785 2.790 2.795 2.9

100 3.1

MaximumTemperature Conductivity

(°C) (µS/cm)

Example: Temperature is 83.7°C and uncompensated conductivity is 1.7 µS/cm. The limit is 2.7 mS/cm at 80°C. PASS!

Stage 1: Temperature/Conductivity Requirements(for non-Temperature Compensated Conductivity Measurements)

• Real-time process (conductivity and temperature!) information.

• Immediate alarms and control options.

• Data can be logged . . . provides a water history.

• Easier and cost-effective.

• Eliminates sample collection and transportation errors.

• Temperature-compensated conductivity remains an excellent technique to observe water quality changes.

Advantages of On-line, In-line Stage 1 Testing

<645> Stage 3 and EP Conductivity Limits at 25°C Stage 3: pH/Conductivity Requirements(for atmosphere-equilibrated samples only)

5.0 4.75.1 4.15.2 3.65.3 3.35.4 3.05.5 2.85.6 2.65.7 2.55.8 2.45.9 2.46.0 2.4

6.1 2.46.2 2.56.3 2.46.4 2.36.5 2.26.6 2.16.7 2.66.8 3.16.9 3.87.0 4.6

Example: Off-line uncompensated conductivity at 25°C is 2.5 µS/cm. Add KCl, and measured pH is 5.5. The limit is 2.8 µS/cm. PASS!

MaximumpH Conductivity

(µS/cm)

MaximumpH Conductivity

(µS/cm)

• Lack of reproducible results between different manufacturers

• Reproducible results in uncompensated mode

• Impurity not consistent

Why did the USP not permit temperature compensation for <645>?

• Eliminates the temperature effect on a measurement

• Provides a fixed threshold for controls/alarms

• Provides a universal reference point, i.e., 0.055 µS/cm (18.2 MΩ-cm) for ultrapure water at 25°C

• Fast, easy, eliminates operator error

• Ideal for QC at each purification step

• Make full use of modern microprocessor capabilities

Why make a “Temperature-Compensated” Resistivity Measurement?


50 50 °°CC

200 200 uSuS/cm/cm

Conductivity value at temperature? 25 C compensate25 C compensateBase on Base on

temperature coefficienttemperature coefficient

“Temperature-Compensated”•• Conductivity measurements depends on temperatureConductivity measurements depends on temperature

the mobility of ions increases at higher temperaturethe mobility of ions increases at higher temperature

resistance in a solution decreases at higher temperatureresistance in a solution decreases at higher temperature

conductivity increases at higher temperatureconductivity increases at higher temperature

•• The extent of increasing the conductivity per The extent of increasing the conductivity per °°C is expressed by theC is expressed by thetemperature coefficient temperature coefficient aa. Usually, . Usually, aa is between 1% and 3% per is between 1% and 3% per °°C.C.For ultra pure water the change per For ultra pure water the change per °°C is between 7.4% at 0 C is between 7.4% at 0 °°C and C and 2.3% at 100 2.3% at 100 °°C. C. The curve is not linear.The curve is not linear.

•• EG. Ultrapure water 0...1EG. Ultrapure water 0...1°°C temperature chanC temperature changing 7.4%, 99...100 ging 7.4%, 99...100 °°C C changing 2.3%changing 2.3%

“Temperature-Compensated”

Reference temperature- 20 Degree C- 25 Degree C

A) Buffer solution 1,413 uS/cm at 25 Cvalue at 40 C

B) Cooling water 1,413 uS/cm at 25 Cvalue at 40 C

Depend on temperature coefficient (%/C) of solutionDepend on temperature coefficient (%/C) of solution

Same meter (same temp coefficient program)

“Temperature-Compensated”

• USP <645> has two tables of conductivity limits – Permits on-line test from 0-100°C.– Permits off-line tests and accounts for innocuous CO2 at 25°C.

• EP 2.2.38 has two conductivity limits– 1.1 µS/cm at 20°C for WFI.– 4.3 µS/cm at 20°C for Purified Water.– Retain nitrate test.

Will this change? YES!

Harmonization for Conductivity Limits

Latest harmonization EP and USP pharmaceutical 2004

Meter Calibration/Performance

• Reports uncompensated conductivity or resistivity.

• Display resolution of 0.1 µS/cm minimum. 1 µS/cm resolution is unacceptable.

• Verify performance to ±0.1 µS/cm by replacing sensor with precision (0.1%) resistor. For example: 100 kΩ resistor with 0.1 cm-1 cell constant should display 1.0 ± 0.1 µS/cm.

• Temperature measurement circuit should be verified.

Calibration and Equipment Specification <645>


Sensor Calibration/Performance

• Cell constant accurate and known to ± 2%.

• Calibrate sensor in a solution with a stated conductivity (from NIST, chemical supplier, etc...).

• Calibrate sensor in a solution prepared to a specific conductivity (ASTM D1125-95 standard or ultrapure water).

• Calibrate sensor vs. another calibrated sensor (from mfgr. usually).


Cell Calibration Methods• Calibrate in a solution vs. a standard sensor

– in the same fluid– in the same container– at the same temperature– compensation disabled

• Calibrate in a solution of known conductivity– procure solution of known conductivity– prepare solution of known conductivity, i.e. ASTM standard methods* or

ultrapure water**

• Send it back to Manufacturing* "Standard Test Method for Electrical Conductivity and Resistivity of Water", American Society for Testing and Materials, D1125-95, 100 Barr Harbor Drive, W. Conshohocken, PA, 19428-2959 (1995).

** K.R. Morash, R.D. Thornton, C.H. Saunders, A.C. Bevilacqua, and T.S. Light, "Measurement of the Resistivity of High Purity Water at Elevated Temperatures", Ultrapure Water, 11(9), pp. 18 26, December, 1994.

Calibration for Conductivity


RequirementRequirementSampling portSampling portStandard cell ASTMStandard cell ASTMStandard transmitter traceable NISTStandard transmitter traceable NIST


Calibration for Conductivity Calibration for Conductivity


Parameter USP EPConductivity test required yes yesEliminate wet tests yes noSeparate limits for PW and WFI no yesOff-line test at temp 25°C* 20°COn-line test 0-100°C** none?Instrument requirements yes no

* table of values, pH dependent** table of values, temperature dependent

EP and USP requirment comparision (Conductivity)

Parameter USP EPSensor accuracy 2% 5%Sensor calibration method not specific specificCalibration solutions user selected specificMethod works 2 stds invalidCompensation none ?Method tested yes no

EP and USP requirment comparision (Conductivity)

0.0900

0.0920

0.0940

0.0960

0.0980

0.1000

0.1020

0.1040

0.1060

0.1080

0.1100

Mar-95 Dec-95 Jun-96 Jan-97 Feb-98 Feb-99 Feb-00

Calibration Date

Cell

Cons

tant

(/c

m)

18.2 Mohm-cm at 25°C40 Mohm-cm at 10°C10 Mohm-cm at 37°CASTM Solution D at 146.93 uS/cmASTM Solution C at 1408.8 uS/cmAverage

Calibration for Conductivity Yearly Change of Cell

Meets and Exceeds specification of proposed method

Requirement USP <645> METTLER TOLEDO

Cell constant accuracy ± 2% ±1%Instrument resolution 0.1µS/cm 0.0001µS/cmInstrument accuracy ±1.0% ±0.3% / ±0.5%Instrument range ~102 105 - 106

Temperature Must read Uncompensated &Compensation Uncompensated Compensated

Instrument ±0.1% ±0.08%, Cell & Tempcalibration resistors NIST traceable


• Prior to November 1996, the existing test for “oxidizable organics”was the Oxidizable Substances test. The test is based on the appearance or disappearance of a pink color.

• November, 1991 – TOC proposed to replace oxidizable substances test.

• Same goals as Conductivity – Replace existing tests with a better test.

• In November 1996, <643> TOC was established as an option to the Total Oxidizable Substances test.

• In May, 1998, the Total Oxidizable Substances was deleted (for bulk water testing). Only <643> TOC is required.

6. Total Organic Carbon (TOC)

• Old tests are qualitative, pass/fail, operator dependent, and labor intensive

• TOC is semi-quantitative, ideal for QC, on-line, capital intensive

• TOC has been a reliable tool in Semiconductor, Power and Pharmaceutical facilities

Reason for Changes


• TOC is a new test method.– Advantages: semi-quantitative, on-line, and process controller.– Disadvantages: cost and difficulty to calibrate/maintain.

• On-line capable of sub-ppb detection limits, fewer problems from contamination

• No single technology for TOC measurement– Lab instrumentation– Membrane-based conductometric– Conductometric

• Capable of on-line QC, QA

TOC Basics

There are 3 basic types of contaminants:

1.) Inorganic: ionic/conductive

2.) Organic: non-ionic/conductive

3.) Typically carbon based particulate

TOC Basics

Total Organic (or Oxidizable) Carbon and is the measure of Organic contaminants.

Organic contamination can come from:

Leaching, shedding or failure of components in the purification and distribution system

Feed waterFormation of biofilms

TOC Basics

Organic contaminants are typically non-ionic and not detected by conductivity instrumentation.

Low conductivity could still mean high levels of TOC (and vice versa)

TOC measurements are used to monitor various stages of water purification processes (just like conductivity)

TOC Basics

What does this mean??What does this mean??High TOC’s translate into high $$ and can:

-Degrade water purification system

-Reduce semiconductor yields

-Contaminate pharmaceutical batches

-Damage power & steam generation equipment

TOC Basics

Total Organic CarbonTotal Organic Carbon- Several molecule size- Differential kind of chemical bonding eg.C=C- Non-conductive mostly present- Non purge able and purge able typical- Various oxidation form- Bacteria example idea 1,000,000 unit mean

1ppb (Amount of bacteria as low resolution)- Simple treatment by Membrane, UV oxidation,

etc.

TOC Basics


Total Inorganic CarbonTotal Inorganic Carbon- CO2, HCO3, CO3- Conductive ion- Detectable by EC meter

(Conductivity/Resistivity)- Interchange by pH value

TOC Basics

TOC Principle

• CxHyOz CO2 + H2O H2CO3 H+ + HCO3-

• Basic calculation TC = TOC + TIC

• TC = Total carbon

• TOC = Total Organic Carbon

• TIC = Total Inorganic Carbon

1) Oxid

ize2)

Detect

TOC Basics

Most Common Technologies for TOC

• UV Oxidation method– TOC Low ppb high accuracy with low maintenance

• Chemical oxidation– TOC High-Low range high maintenance and additional chemical

reagent requirement

• Combustion– TOC High-Low range high maintenance and high temperature

operation

1) Oxid

ize

TOC Basics

Most Common Technologies for TOC

• Conductivity– Detect TOC TIC (Conductive) Recalculate to TOC

• NDIR– Gas detector by N2 as the carrier

• Membrane base– Similar to DO electrode which use selective gas membrane base

2) Dete

ct

TOC Basics

TOC Instrumentation Requirements forUSP <643> TOC and EP 2.2.44

• Limit of Detection of 0.050 mg/L (50 ppb)

• Calibrate according to Manufacturer’s recommendations

• Must meet System Suitability testing periodically

Requirements

System Suitability for USP <643> and EP 2.2.44

• Measure TOC of 0.50 mg carbon/L (as sucrose), Rs.

• Measure TOC of 0.50 mg C/L (as p-benzoquinone), Rss.

• Measure TOC of water used to prepare these solutions, Rw. Not to exceed 100 ppb.

• Response shall be between 85 and 115%!

• TOC shall not exceed user limit, Ru = Rs – Rw (near 500 ppb)

⎟⎟⎠

⎞⎜⎜⎝

⎛−−

×=ws

wss

RRRR100Response

Requirements


PW and WFI Water Requirements for TOC

• Procure sample. Measure TOC of test water, Ru.

• Compare Ru to system response at limit, Rs-Rw. (~500

ppb).

• Water passes TOC test if Ru < Rs - Rw.

• Not required for EP Aqua Purificata (PW).

Requirements

EP JP USP1. Clarity + Not tested Not tested2. Colour + Not tested Not tested3. Extractable volume + Not tested Not tested4. Nitrate + ≠ EP Not tested5. Heavy metals + ≠ EP Not tested6. Aluminium + Not tested Not tested7. Acidity/alkalinity + ≠ EP Not tested8. Conductivity + Not tested Not tested9. Oxidisable substances + = EP = EP10. Chloride + ≠ EP ≠ EP ≠ JP11. Residue on evaporation + = EP Not tested12. Sulphate + ≠ EP ≠ EP ≠ JP13. Ammonium + ≈ EP ≈ EP14. Calcium/Magnesium + Not tested Not tested15. Calcium Not tested Not tested +16. Bacterial endotoxins + = EP = EP17. Particulate contamination + Appears to be the same,

detailed check still necessary Not tested

18. TOC Not tested at this level + ≠ EP & USP bulk waters Not tested at this level

19. pH value Not tested Not tested +20. Carbon dioxide Not tested Not tested +21. Sterility + ≠ EP ≠ EP ≠ JP

Comparison of Sterile WFI Water Requirements

USP Packaged Waters Initiative

• Goal: Replace the wet chemistry tests with something more reliable, faster, better

• Issues– TOC and conductivity and pH. Are they the right

measurements?– What are the limits?– Should the limits be the same as the bulk material?– Can we eliminate all wet chemistry tests?

Packaged Waters pH Range

• Goal: Determine the correct pH Limits for each type of Packaged Water

• Issues– Glass containers leach NaOH and raise pH. Is this a problem?– Plastic containers leach TOC. Is this a problem?– Is this a water problem or a packaging problem?– Size Does Matter!

• Argument: If used as a diluent, should we be so restrictive on limits?

• Action: Publish stimuli article and review responses

TOC of Sterile Packaged Waters Steam Definitions

• Clean Steam is the condensate of…– water that would meet requirements for Purified Water– water that would meet requirements for WFI– steam prepared from Purified Water– steam prepared from WFI

• Pure Steam is the condensate of…• Steam is defined by the quality of the condensate?• Steam is defined by the quality of the feedwater?• Steam is defined by the quality/method of preparation?

There is no accepted definition!


Summary

• The USP requires that Purified Water and Water for Injection meet specific conductivity and TOC requirements.

• USP <645> is a 3 stage conductivity test that permits on-line and off-line testing. Pass any stage and the water meets the conductivity requirements.

• USP <645> requires the use of non-temperature-compensated conductivity measurements.

• There are specific performance requirements for the instruments.Not all analyzers meet these requirements.’

Harmonization is coming!(it’s just that no one seems to know how long it will take!)

Appendix I

- EHEDG

- 3A

- USP FDA O-Ring

- PEEK FDA

- 3.1B

- PED Pressure resistance certified

% Rejection % Recovery

Grain monitoring for DI

Grains = ∫ Flow x TDS dt

Grains - cumulative TDS or ion loadFlow - flowrate entering DI bedTDS - total dissolved solids based on

conductivity entering DI bed

Deionization Capacity MonitoringDICapDICapTMTM

Last page

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