1. The Traceability of Conductivity Meter and Cell Calibration in the Low Conductivity Ranges Jun Bautista, Director, Genzyme Metrology Genzyme Corporation, A Sanofi Company 21 August, 2011

2. Topics For Consideration  Traceability  General Issues  Regulatory Issues  Program Issues  Technical Issues  Special Interest Issues

3. Traceability  1875 the need for “consistency and uniformity” in measurements was recognized and formalized internationally  Traceability is needed: 1. Laws and contracts require it 2. Customers ask for it 3. Standards specify it 4. Accreditation bodies look for it- ISO/1EC17025, sec. 5.6 5. Quality measurements ensure it

4. Traceability in Measurements Concept  Unbroken chain of comparisons to national or international standards (SI) with each comparison measurement having stated uncertainties  Traceability to an SI through a National Measurement Institute (NMI), e.g., NIST, NPL, PTB, etc…

5. Elements Critical in Establishing Traceability 1. Realization of SI units 2. Unbroken chain of comparisons to NMI 3. Uncertainty of measurements at each step of the traceability comparison reported overall uncertainty for the entir series of comparisons 4. Technical competence in the performance of measurement comparisons through accreditation 5. Accepted and documented measurement comparison procedures 6. Repeatability of measurement comparisons at pre-determined intervals premised on the measurement uncertainty required, frequency of use, stability of standard and the measurement device 7. “Measurement assurance” program for each step in the traceability chain

6. General Issues  Lack of documented evidence and traceability to national or international measurement standards  Lack of a reference material or reference methods suitable for low conductivity ranges  Lack of reference solution to calibrate conductivity measuring devices used at low conductivity ranges with low uncertainties  No accredited laboratory can actually propose calibration for < 1µS cm -1 at 25.0° C

7. Regulatory & Accreditation Issues  US Pharmacopoeia, EU Pharmacopoeia, European Directorate for Quality of Medicines (EDQM), 21 CFR 211.194 (a) sub-clause 2  Software Validation  Method Validation  Instrument Qualification  ISO/IEC 17025

8. Program Issues  Evaluation of Good/Bad Manufacturer/Models  Transfer of Methods  Proficiency Testing  Inter-Laboratory Comparisons  Guidance on Vendor Selection  Calibration Interval Determination  Due Date Extension  Out-of-Tolerance Notification/Investigation

9. Technical Issues  Measurement Assurance Activities  Measurement Assurance Risk Analysis  Measurement Uncertainty Program Development  Acceptability of Tolerance Testing (where it is useful)  Criticality Testing  Simulation Type Calibrations  Decision Risk Analysis

10. Special Interest Issues  New Metrological Approach - PTB in collaboration with Millipore designed, built, and method validated a primary flow-through conductivity cell determined geometrically (concentric electrodes) - Developed as an in-line calibration method based on a primary method that provides users with a metrologically recognized calibration method for conductivity measuring devices in the low conductivity ranges

11. Special Interest Issues contd..  Results of PTB/Millipore Collaboration - Lack of aqueous reference standards due to the instantaneous contamination of high purity water carbon dioxide from the air, ions from container, and from ideal environment resulted in the use of ultra-pure water (UPW) –based calibration method for calibration and validation of conductivity values displayed by conductivity meters in the low conductivity ranges - UPW has a nominal conductivity of 0.055 µS cm -1 at 25.0°C and a Total Organic Carbon (TOC) below 5 µg l -1 - The current detection sensitivity of most conductivity meters show no effect on the conductivity value as long as the ionic contamination remains below 1 µg l -1 NaCL overall equivalent - Not without weaknesses and limitations, e.g., multiple purifications, 0.22 µm membrane filtration, UV photo oxidation, etc…, metrologically, this method remains the most acceptable until reference solutions can be proposed and produced.

12. Special Interest Issues contd.. - Most common application of UPW in the calibration of conductivity meters in the UPW range is through an in-line design using conductivity cells with concentric electrodes to minimize electromagnetic interference - Concentricity of electrodes is geometrically traceable, impedance bridge connected to the cell, cables, and temperature sensors have traceable calibrations, and resistance of UPW is measured and converted to conductivity (uncompensated for temperature) and performed at a temperature that can be accurately controlled with a known uncertainty - Therefore, cell dimensions, resistance, and temperature measurements are fundamentally traceable to the SI, the conductivity of UPW may be deemed determined by a primary method of measurement...

13. Traceability of Conductivity Measurements in the Low Conductivity Range - Next Steps  Solicit volunteer companies to build a “concentric cell” conductivity measurement system (see PTB/Millipore design)  Submit models for evaluation by peer companies/NIST  Proficiency Testing  Inter-Laboratory comparisons  Report results to NIST, NCSL, MSC, USP, FDA etc…  Transfer of Validated Method(s)  Establish an on-line forum e-mail address. Use Jun Bautista as focal point of contact at: jun.bautista@genzyme.comjun.bautista@genzyme.com  Jun Bautista to establish a Linked In Conductivity Measurements Discussion Group

14. …for your attention Thank you….