1. USP and EP Water Systems
TOC and Conductivity
for
USP and EP Water Systems

2. Content
Conductivity
TOC analysis
Validating a TOC analyzer
Introduction to the PAT700 combined TOC and Conductivity Analyzer

3. Dissociation and Conductivity
Conductivity measures ionic activity
Ionic compounds dissociate into ions, then re-associate back into the compound
E.g. Sodium Chloride (NaCl) made from Na+ and Cl-
Add energy and the Na+ and Cl- split, or dissociate
The ions then contribute to the conductivity of the water
Some substances dissociate more readily and contribute more strongly to conductivity
Different temperature compensation curves for different waters

4. Conductivity
Conductivity Meter
Na+ +
Cl- - + -
Measurement
Cell

5. Conductivity varies with temperature
Conductivity = TOC
Temperature fluctuations during the TOC measurement can have a large effect on the accuracy of the measurement. So, for the purposes of measuring TOC, we used measure the sample temperature and use temperature compensated conductivity.
However, for the purposes of measuring and reporting conductivity, the pharmacopoeias state that the conductivity measurement must be reported without temperature compensation. So we can provide uncompensated conductivity results from the Anatel too.
Temperature

6. USP<645> Conductivity & Temperature
Conductivity meters will report different results depending on:
The compounds present in the water
The temperature compensation curve selected
Hence pharmacopoeias call for un-compensated, e.g. USP<645>:

7. Content
Conductivity
TOC analysis
Validating a TOC analyzer
Introduction to the PAT700 combined TOC and Conductivity Analyzer

8. On-line TOC analysis – principle of operation
Conductivity Meter + -
On-line TOC meters for pharmaceutical grade waters are based on conductivity instruments. A sample of water is taken and the conductivity measured. The initial conductivity is caused by any trace inorganic materials in the water, such as dissolved carbon dioxide. Any organic materials present will not contribute to the conductivity at this stage.
Conductivity varies with temperature, so we have a very accurate temperature sensor built into the measurement cell.
Measurement
Cell UV
lamp

9. On-line TOC analysis – principle of operation
Conductivity Meter
Organic material
turned to CO2 + - + - UV
To measure the TOC, we convert all the organic material in the sample to carbon dioxide using ultra-viloet light in the presence of a titanium catalyst.
An ultra-violet lamp is used to cause all organic materials to oxidise to carbon dioxide. The resultant increase in dissolved carbon dioxide contributes to an increase in conductivity. This increase in conductivity is directly proportional to the amount of TOC originally present in the sample. UV

10. On-line TOC analysis - Principle of Operation
Organics oxidised to CO2
Conductivity
d conductivity = TOC
This is a graphical representation of the oxidisation process. Initially, the conductivity of the water sample is measured to establish a base line. Then the ultraviolet lamp is turned on. The A643a monitors the changing conductivity as the organic materials in the sample are oxidised to carbon dioxide. When there are no further changes in the conductivity, the analyser measures the new conductivity and compares it with the base-line conductivity. The difference in conductivity is directly proportional to the organic materials trapped in the water sample.
UV on
Time

11. Letter of the Law
USP (‘till recently) “… share the objective of completely oxidizing the organic molecules in an aliquot of sample water to carbon dioxide…”
EP states “… have in common the objective of completely oxidizing the organic molecules in the sample water to produce carbon dioxide…”
Only Hach’s, End Point Detection method, strictly meets this requirement for online TOC analyzers
Anatel’s dynamic endpoint detection determines when the oxidation has been completed. The four identified curve types indicate that some organics are easily oxidized by UV and some are not. Even at low levels the organics that exist in pharmaceutical waters may take up to 20 minutes to completely oxidize. Flow-through systems on the other hand cannot completely oxidize but must extrapolate out the answer. Sievers residence time is 6 minutes. Sievers patent application process claimed some TOC takes up to 40 minutes to oxidize with UV alone. Thornton residence time is 3 minutes. Thornton(T&C) try to claim that the USP will accept oxidation to organic acids, but that does not technically meet the USP and the FDA is the final decision maker so better meet the letter.

12. Dynamic End Point Detection
Although the photocatalytic oxidation process is extraordinarily efficient, different types of organic compounds show different profiles as a function of time vs conductivity as a result of oxidation. We report, with each sample, the type of oxidation profile as a P1, P2, or P3.
The P1 profile is the “simplest” and most common and represents the conductivity vs time curve for short chain, single- bond carbon compounds. The conductivity increases quickly and then levels as oxidation reaches completion. P1 profiles typically represent low molecular weight carbon compounds at concentrations >20 ppb. Obvious exceptions are acetone and isopropanol which form difficult-to-oxidize acetic and formic acids respectively. These compounds typically display a P3 profile.
The P2 profile represents a condition where a background source of organics such as diffuse CO2 or the oxidation products of components such as seals and gaskets within the analysis cell cause an increasing conductivity value that indicates a non-ending oxidation. However, the algorithm that monitors the conductivity change as a function of oxidation can determine the difference between the oxidations of the background and other organics present by calculating the first and second derivatives of the reaction plot. The correct TOC values are therefore calculated and reported. P2 profiles are possible only at low concentrations, almost always <25 ppb and associated with semiconductor UPW..
The P3 profile indicates the presence of intermediate oxidation products that have a higher conductivity than the final product. Again, the software monitors the reaction curve and "senses' this special condition and waits until the conductivity stabilizes and Ievels before making the final TOC calculation. P3 profiles always indicate a concentration >1.5 ppb.
The P1, P2, and P3 are qualitative indicators of the current status of the water. A change in profiles is more important than the actual profile itself because it indicates that something significant has changed in the water system. The two most important factors for “diagnosing” or recognizing significant change are an increase/decrease of TOC and a profile change.
USP <643> Requirement: Instrument Must Completely Oxidize the Sample

13. Content
Conductivity
TOC analysis
Validating a TOC analyzer
Introduction to the PAT700 combined TOC and Conductivity Analyzer

14. Validating the TOC analyser
Validate that the instrument matches the URS
Validate that installation is as per manufacturer
Verify Calibration
TOC
Conductivity
Temperature sensor
System suitability
Verify connections to remote systems
Performance qualification
Calibration is stable
Analyser works correctly

15. Tests to validate the analyser
Validate that the instrument matches the URS
Validate that installation is as per manufacturer
Verify Calibration
TOC
Conductivity
Temperature sensor
System suitability
Verify connections to remote systems
Performance qualification
Calibration is stable
Analyser works correctly

16. Validation documents & procedures
Demonstrate URS requirements are met through, Commissioning, IQ and OQ
PQ demonstrates that the analyzer is stable and can support required calibration and system suitability intervals
Week 1
IQ, Commissioning
6 monthly
testing
First 4 weeks
Calibration stability, System suitability

17. Tests to validate the analyser
Verify that the instrument matches the URS
Verify that installation is as per manufacturer
Verify Calibration
TOC
Conductivity
Temperature sensor
System suitability
Verify connections to remote systems
Performance qualification
Calibration is stable
Analyser works correctly
In today’s presentation, we are going to focus on verifying the calibration, system suitability and verifying remote connections.

18. TOC Calibration – factory & on site
Factory Calibration
0 Reported TOC 1000
When the analyser is manufactured it is calibrated on a test bench in our factory laboratory. The analyser is calibrated to +/-1ppb accuracy over the range 1ppb to 1,000ppb. Calibration on site is by analysing three certified standards traceable back to USP starting materials (USP requirement).
0 Injected TOC 1000

19. TOC Calibration on site
750ppb
500ppb
250ppb
The TOC analyser is used to demonstrate that the water system is in compliance and that the TOC levels do not vary above the 500ppb limit.
In this graph the blue line represents a typical water system TOC level.
Because we are interested not in the exact water system TOC level, but only that it does not drift above the 500ppb mark, the area we are interested in calibrating is around the 500ppb level.
So, we calibrate using certified standards, traceable back to USP starting materials. We include a 500ppb standard and then ‘bracket’ the 500ppb point using 250ppb and 750ppb standards to provide a three point calibration based around the 500ppb limit.
Water system TOC value – modern system = 30 to 70ppb

20. Certified traceable standards
The calibration kit consists of 3 vials of certified sucrose standards, traceable back to USP starting materials, with a concentration of 250, 500, and 750 ppb carbon +10%. The calibration kit also includes a vial of reagent water for measuring and establishing the reagent blank and all of the kits are shipped with a Certificate of Analysis.
The validation kit includes a vial containing 500 ppb carbon (sucrose), and a second vial of reagent water for determining the sample blank value. The validation control standard is designed to confirm conveniently the integrity of the calibration curve and even be used as an indicator for when a new calibration may be necessary.
The System Suitability Kit includes a vial of sucrose at 500 ppb carbon for determining the Standard Solution response, a solution of 1,4-benzoquinone at 500 ppb carbon for determining the System Suitability Solution response and a vial of reagent water for determining the Reagent Water Control. The sucrose and 1,4-benzoquinone are prepared from USP (RS) reference standard materials as specified by the <643> TOC method.
Anatel also provides an electrolyte solution at approximately 100 µS/cm for confirming the cell constant. The actual value is stated on the supplied certificate of analysis and is inputed into to the analyser via the user interface screen. The solution calibration is traceable to NIST. There is also a NIST resistor available which can be used to follow the tests in USP<645> for checking the conductivity meter accuracy.

21. Calibration – As Found, As Left

22. System Suitability Test Must Be Performed
System Suitability is not calibration!
System suitability is “the process of validating whether your system (i.e. TOC analyzer) is acceptable for providing useful analytical data without any bias.”
This is typically done by:
Analyzing a material that is easy-to-oxidize (sucrose)
Analyzing a material that is difficult-to-oxidize (1,4 - benzoquinone)
Calculating the ratio of the responses
The System Suitability is intended to demonstrate that the instrument system that is being used does meet the USP <643> requirements. It is not a calibration but rather a test that “proves” that the equipment can measure a difficult-to-oxidize (measure & within +/- 15%) as well as an easy-to-oxidize organic compound.
Once the test has demonstrated that the system is suitable for the <643> measurement, it is not necessary to repeat the test to prove it again, less some significant event that could affect the instrument has taken place.
We recommend a System Suitability frequency ranging from once per month to 4 – 5 times per year.

23. System suitability – USP<643> & EP2.2.44
System suitability is not a calibration. The pharmacopoeias require that any TOC analyser is capable of accurately analysing the full range of organic materials that may occur in pharmaceutical-grade water systems. So, the System Suitability test was devised. In this test the analyser is challenged with both a simple to oxidise carbon (sucrose) and a difficult to oxidise carbon (1-4benzoquinone). The results from the two analyses are compared and the pass/fail criteria is the ability of the analyser to deliver a similar result for both compounds. The results of the two analyses must be within the range of 85% to 115% of eachother.

24. System suitability calculation
Sucrose analysis result = 475ppb TOC
Benzoquinone analysis result = 485ppb TOC
Calculation = Sucrose = = >85%<115%
Benzoquinone
The system suitability calculation is based on a comparison of the analyser’s ability to oxidise a simple organic compound (sucrose) and a difficult to oxidise compound (benzoquinone). Notice that the analyser does not have to correctly analyse the standard solutions, it just needs to analyse them both the same. So in this case you can see that the analyser has reported TOC levels of 475ppb and 485ppb respectively, whereas the true certified value of the standards is actually 500ppb. Just so long as the analyser measures both compounds equally, it will pass the system suitability test, even though the reported results may not reflect the actual TOC values of the standards. System suitability is not a calibration and does not demonstrate that the analyser has fully oxidised all the TOC. The system suitability calculation compares the TOC analysis results between the two compounds. Provided the result is between 85% and 115%, then the analyser is deemed suitable for analysing the full range of organic materials that might be found in pharmaceutical grade waters.

25. Verifying conductivity – USP<645>
Verify meter accuracy (+/- 0.1mS)
Verify cell constant (+/-2%)
Verify temperature sensor (compensation)

26. Temperature sensor verification
Conductivity of a water sample varies widely with temperature. The pharmacopoeias ask that conductivity values are reported uncompensated, i.e. that the temperature of the sample is not taken into account. However, the TOC analyser uses conductivity to calculate the amount of TOC present, so a very accurate, temperature compensated conductivity is required as the water sample temperature will vary during analysis. For this reason, as part of the validation of the Anatel TOC analyser, we carry out a verification test of the analyser temperature sensor using a NIST-traceable temperature device.

27. Verifying conductivity – meter accuracy
Accuracy of
meter

28. Verifying conductivity – meter accuracy
Disconnect measurement cell

29. Verifying conductivity – meter accuracy
Meter = Resistor +/-0.1mS
Replace cell with
NIST traceable resistor

30. Verifying conductivity – cell constant
Function area and distance
Area
Distance

31. Verifying conductivity – cell constant
Introduce certified conductivity standard
+/-2% of certified standard
Cell constant known within +/-2%

32. Content
Conductivity
TOC analysis
Validating a TOC analyzer
Introduction to the PAT700 combined TOC and Conductivity Analyzer

33. PAT700 TOC Analyzer with OASISTM
Onboard, Automated Standards Introduction System

34. Introduction to the ANATEL PAT700
On-line TOC analysis with complete sample oxidation
OASISTM Onboard, Automated Standards Introduction System
Calibration and system-suitability test SOP built-in via color touch-screen
Individual 4-20mA outputs for TOC, temperature and conductivity
Main and standby auto-switching UV lamps with UV Detect™ technology
IP 56 stainless-steel enclosure improves protection from water and particulates

35. PAT700 – Supports all test requirements
USP <643> Total Organic Carbon
USP <645> Conductivity
USP <788> Water for Injection
USP <789> Opthalmic Water
EP Conductivity
EP Total Organic Carbon
JP <60>
21 CFR Part 11

36. OASISTM Technology
Saves time and delivers improved confidence in quality
All bottles for a test installed at once and tests automated
Information about each standard stored in RFID tag on the bottle
contents, concentration, certified value, lot number, expiration date
(Manual data entry possible for customer prepared standards)
Analyzer voids bottle following test
OASIS can be used for grab sample analysis

37. Non-Hach Standards Warning Message
If the user selects “No”, then the test is cancelled and the user is placed back at the Run Standards selection screen. 
If the user selects “Yes”, then the user is prompted to enter all of the bottle information manually and the test is allowed to continue as if the bottle did not have an RFID tag at all.

38. PAT700 TOC Analyzer with OASISTM
Grab-sample analysis

39. Grab Sample Analysis Utilizes OASIS sample bay
Up to 4 grab sample bottles at a time
Grab Sample Bottle ID nine character alphanumeric
(ex. PW POU 01 )

40. PAT700 TOC Analyzer with OASISTM
OOS sample capture and root-cause analysis support

41. OOS sample capture capability
Utilizes OASIS sample bay
OOS triggers automatic collection of two samples
Re-tests 1 bottle to confirm OOS
Saves one sample for analysis in laboratory to support root-cause analysis

42. PAT700 TOC Analyzer with OASISTM
21 CFR data export

43. 21 CFR Part11 Data Export TOC Dataview PC Software
Allows the viewing of encrypted data
Allows decrypted data to be saved
Encrypted file exported as filename.hef
Read-only .pdf for record retention
.txt files to load into LIMS database

44. PAT700 TOC Analyzer with OASISTM
Clean-In-Place verification

45. On-line Monitoring of CIP Final Rinse Water Verification
Conductivity can be used for detecting acid wash residues
TOC can be used as broad-spectrum test to detect presence of drug material residues
Unit programmed to meet user’s specific criteria
Either conductivity threshold
Or time based
After TOC analysis, reports results and return to idle mode

46. On-line Monitoring of CIP Final Rinse Water Verification
Automated Mode (plc controlled):
Unit idle until called for
TOC analysis triggered via:
Digital input, or
Serial command, or
Modbus over Ethernet
Reports results and return to idle mode

47. PAT700 TOC Analyzer with OASISTM
Laboratory TOC analysis

48. PAT700 with auto-sampler
Autosampler for laboratory use can load up to 36 vials
e.g. point-of-use and rinse water samples.(0-2000ppb)
Provides a laboratory TOC analyzer without reagents or carrier gas

49. PAT700 TOC Analyzer with OASISTM
Water loop monitoring and root-cause analysis support

50. Dual-stream option PAT700
Two inputs
One on the PW/WFI loop start, one on the return
Brackets loop quality
Helps root-cause investigation to find contamination source, e.g. feed-water or point-of-use

51. Bracketing POU for On-line Release
Contamination
Source ?
Points-Of-Use (POUs)
Contamination
Source ?
Pure Steam
Generation
Distillation - WFI

52. PAT700 TOC Analyzer with OASISTM
12-month service and calibration intervals

53. UV DetectTM Diagnostics
Direct measurement of UV source performance
Diagnosis of UV status
Fast, real-time lamp feedback
On-line: Verified after every TOC analysis
Off-line: Can be conducted in diagnostic mode after lamp replacement
Detects rouge contamination
Provides confidence for on-line water release
Standby UV lamp automatically switched on if main lamp fails – avoids gaps in analysis data
More reliable than simple “hours-of-operation” counters
Reduces cost-of-ownership – analyzer can support 12-monthly calibration and service intervals

54. Questions?
PAT700 TOC and Conductivity Analyzer