meeting u.s. regulations with instrumentation laboratory’s .../media/il/docs/product... ·...

Revised July 2007

Meeting U.S. Regulations with Instrumentation Laboratory’s GEM®Premier™

4000 with Intelligent Quality Management (iQM®)

R. H. LAESSIG, Ph.D. AND S.S. EHRMEYER, Ph.D.†

HISTORICAL Concurrent with the analysis of patient specimens, laboratories analyze “control materials” to validate the quality of test results. Quality Control (QC) materials with “known” values simulate actual patient specimens. Achieving correct results on the QC materials is evidence that the test system is functioning properly and that patient test results are valid. REGULATIONS Prior to the Clinical Laboratory Improvement Amendments (CLIA’88), laboratory directors and volun- tary accreditation programs, such as the College of American Pathologists (CAP) and the Joint Commission (JC), determined the number, frequency and performance limits for the analysis of QC products. Current CLIA QC regulations (revised January 24, 2003) specify the minimum frequency and levels (concentrations) of QC to be run. They also require test-site directors (or designates) to establish the performance limits as part of their on-going responsibility to ensure test quality. With today’s instruments, these regulatory requirements often are met by simply following the manufacturer’s directions. To be in compliance with these regulations, a test site must ensure its QC plan requires that: (1) manufacturer’s directions, which include calibration protocols and the prescribed, minimum frequency and levels of QC testing, are followed, (2) QC data are assessed in real-time to ensure validity of patient test results, and (3) appropriate documentation of the quality assurance processes is created and maintained. This includes documentation of any corrective actions. Instrumentation Laboratory’s (IL) GEM Premier 4000 with Intelligent Quality Management system (GEM-iQM system) automatically performs all three of these functions.

† R & S Consultants, Madison, WI

OVERVIEW OF IL’S GEM-IQM SYSTEM APPROACH TO QUALITY CONTROL The GEM-iQM system is a closed, free from operator intervention, and totally automated system that has introduced a completely different approach to assured quality. The GEM-iQM system, which differs markedly from traditional blood gas analyzers, moves the “quality paradigm” forward by using state-of-the-art technology in both instrument design and information processing. Its automated and on-going analysis of Process Control (PC) solutions and continual assessment of all critical measurement components ensures test quality while relieving operators of almost all of the traditional and time-consuming responsibilities associated with QC and many of those relating to traditional quality assurance. In addition to addressing the regulatory requirements (QC and quality assurance practices, etc.), the GEM-iQM system introduces new features including self-initiated QC and function assessment, automated trouble-shooting, clot and interference detection, internal software which ensures fail-safe performance. “Acceptance limits,” a CLIA term, are quality limit specifications based on system performance specifications and defined total allowable error requirements. The GEM-iQM system’s built-in quality assessment functions provide test-site directors, who have responsibility for ensuring the quality of the testing process, a fully-documented means of meeting their appropriate “regulatory” responsibilities. Especially in a near-patient-testing environment, where the primary focus is on patient care, the GEM-iQM system provides directors with assurance that regulatory requirements are fully addressed – yet in a manner completely transparent to the operators.

The latest revisions (2003) to CLIA’88:

The Center for Medicare and Medicaid Services’ compan- ion document to CLIA, Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services, extend the CLIA concepts of QC and quality assurance to quality assessment (QA). The GEM-iQM system contains the requisite levels of liquid QC (called Process Control solutions) in the disposable analytical cartridge to assess for blood gases, hematocrit, metabolites and electrolytes on a 24/7 “ready” basis. The GEM-iQM system automatically performs performance assessments

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at a frequency that exceeds the minimum regulatory man- dates. Each QC result is evaluated against total allowable, error-based tolerance limits. All QC data and assessments of critical analytical components are evaluated, recorded and documented. If the GEM Premier 4000 detects results outside of acceptable performance limits, “corrective actions” are initiated automatically. If “self-correction” is not possible, the affected analyte(s) test channel is disabled, the operator alerted, and full documentation created. This documentation fully meets the regulatory requirements.

The GEM-iQM system’s approach to ensured quality also incorporates new QC paradigms that take advantage of state- of-the-art technology to allow for more effective and automated quality management of the entire analytical process. In real-time, the system monitors its performance in terms of the usual “instrument function checks” -- temperature, reagents, sensors, etc. The GEM-iQM system also is alert to sensor “failure patterns,” which detect clots, interferents, etc., and common operator errors, such as incorrect sample pres- entation, short sampling, inadequate anticoagulant, inadequate mixing of the anticoagulant, sample contamination and clots. Assessment of these specific types of “quality” parameters” were clearly not part of the thought process when the regulations (CLIA) or the rules (CAP, JC, etc.) were created, but certainly are very relevant to total quality management of tests available with today’s state-of-the-art instruments.

Brief overview of GEM-iQM system:

1. Each analytical cartridge has an on-board use-life of up to 28 days (depending on cartridge selection) and contains all the analytical components including sensors, reagents and Process Control (PC) solutions. With each analytical cartridge installation, the GEM Premier 4000 performs an extensive, automated, cartridge-verification process to ensure that all critical measurement components meet the tolerance (acceptability limits) specified by the manufacturer.

2. In addition to the internal cartridge verification conducted on installation, each test site completes the calibration process and final accuracy assessment by analyzing a series of external, NIST-traceable calibrators, called CVP. Once this two-step calibration process is completed successfully, all critical measurement component specifications are locked in memory for the life of the cartridge and these values are the benchmarks for every subsequent quality assessment.

3. The GEM-iQM system is ready for patient sample analysis. Throughout the use-life of the cartridge, on-going QC checks are made, using onboard, multi-level PC solutions that contain the actual analytes being assessed. The frequency of these assessments meet or exceed the required regulatory mandate for QC and monitor the entire analytical process in a very traditional QC format, including following the exact fluidic pathway as a patient sample. In addition, the new, non-traditional QC parameters, continually monitored, introduce a ground-

breaking level of quality management and assurance. No patient test result is released unless the entire test system is within specifications.

4. The GEM Premier 4000 records in memory all checks associated with a particular analytical cartridge. These include every sensor millivolt reading, every QC result, every check on calibration stability, every corrective action, etc. The complete documentation is available for recall by the laboratory director or designee, or the inspector.

SUMMARY We believe that the GEM-iQM system meets the mandated QC practices. In addition, evaluating new and non-traditional quality parameters, not envisioned or described in the regulations, provides a new level of quality management and assessment.

APPENDICES 1-5 The information in Appendices 1-4 focus on, by regulatory agency (CAP, JC, CMS [CLIA], and COLA), the current regulatory requirements and how each is met by the GEM-iQM system. Appendix 5 discusses data that summarize the GEM- iQM system’s performance in proficiency testing or the 2006 CAP Surveys. The discussion addresses six-month calibration verification, as well as the implications of inter-cartridge (cartridge-to-cartridge) consistency. The data establish the basis of the claim that each cartridge change does NOT affect performance. Sharon Ehrmeyer, Ph.D., MT (ASCP), is a Professor of Pathology and Laboratory Medicine and Director of the Clinical Laboratory Science/Medical Technology Program at the University of Wisconsin Medical School in Madison, Wisconsin. Dr. Ehrmeyer currently is the chair of the AACC’s Government Relations Committee, a member of ASCP’s Board of Governors, and the section editor of the Regulatory Affairs column in “Point of Care,” the journal of near-patient testing and technology. Her interests focus on laboratory quality issues including the impact of laboratory regulations on laboratory practices and POCT. She has written numerous book chapters and journal articles and has presented these interests nationally and internationally. Ronald Laessig, Ph.D., is a Professor Emeritus of Pathology and Laboratory Medicine and Population Health Sciences at the University of Wisconsin Medical School in Madison, Wisconsin, and Director Emeritus of Wisconsin's State Public and Environmental Health Laboratory. He served as President of NCCLS (now CLSI), and as a member of the Board of Directors for the AACC. Dr. Laessig is a former member and chairman of the FDA’s In vitro Diagnostic Products Committee and has been a member of numerous committees for the AACC, CAP, CLSI, and APHL. He was princi- pal author of NCCLS’ “Standard on Methological Principles for Assigning Target Values for Calibrators and Controls.” Both author “The Poor Man's (Person's) Guide to the Regulations: CLIA, CAP, JC and COLA” and present numerous workshops on CLIA, QC and quality management.

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Appendix 1

Meeting the College of American Pathologists (CAP) Quality Control (QC) and Performance Specification Requirements

(POC refers to the Point-of-Care Testing Checklist; LSV to the Limited Service Laboratory; CHM to Chemistry and Toxicology; and GEN to Laboratory General. All Checklists are dated October 2006)

CAP Checklist Standard Number

CAP Standard Description

What Sites Need to Do to Meet CAP Standards with the GEM Premier 4000 and iQM (GEM-iQM System)

What Instrumentation Laboratory (IL) and the GEM-iQM System Provide

POC.03500 LSV.00500 CHM.10500

Clearly defined and documented Quality Control (QC) and Quality Management (QM) program to ensure quality throughout the pre-analytical, analytical and post-analytical (reporting) phases of testing

As part of documentation, assemble the QC and QM policies/procedures for the three phases of testing Test-site director or designee documents approval of the GEM Premier 4000’s QC/QA approach, which monitors the entire analytical process, and the QC limits, which are based on total allowable error requirements and instrument performance specifications Maintain records

• QC information in the GEM Premier 4000 Operator’s Manual • QC information in GEM Premier 4000 Standard Operating Procedure (SOP) diskette • GEM-iQM system automatically analyzes a minimum of two levels of PC (QC) solutions every four hours and a third level (for all analytes except Hct) every 12 hours. This exceeds the mandated requirements for all analytes measured • PC solution results are evaluated immediately by the instrument software. The statistical information is updated daily, and can be viewed on demand • GEM-iQM system continually monitors and maintains the stability of the verified calibration to assure on-going accuracy • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • A Delta Chart for each analyte tracks the mean, minimum and maximum analyte values obtained each day for each PC solution and provides an additional performance check • GEM-iQM system immediately alerts the operator when QC tolerance limits are not met • GEM-iQM system documents all PC solution results and any corrective actions taken

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What Sites Need to Do to Meet CAP Standards with the GEM-iQM System

What IL and the GEM-iQM System Provide

POC.04900 & .05000 LSV.36900 & .36840 CHM.12900 & .12600

New reagents validated before or concurrent with use for patient testing. Reagents not used beyond expiration date

Nothing • All required reagents and solutions are contained in the analytical cartridge and IL supplied • Cartridge reagents and solutions are validated extensively by IL before cartridge shipment and again by GEM-iQM with each cartridge installation (start-up), prior to patient testing • Cartridge EEPROM contains cartridge information including expiration date. GEM-iQM does not accept outdated cartridges • Cartridge information is documented and traceable

POC.08200 LSV.40210 CHM.13100 & .34200

High quality materials used for calibration and calibration verification.

Nothing

• With each installation, the sensors in the analytical cartridge are calibrated using two different NIST-traceable solutions

POC.08300 LSV.40530 CHM.13400

Criteria established for frequency of recalibration or calibration verification and the acceptability of results

Perform calibration verification* every six months to revalidate AMR (see Appendix 5 for cartridge-to-cartridge consistency discussion) Assess and approve data; keep records *calibration verification and revalidating reportable range are the same activity for the GEM-iQM system

• A new calibration occurs with each cartridge installation on the GEM- iQM • Cartridge changes do not affect range of reportable results • NIST-traceable Performance Verification Product (PVP) may be purchased from IL (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit)

POC.08600 CHM.13700 (AMR... Range of analyte values that a method can directly measure, without dilution)

Criteria established for validating AMR (reverified at least every six months)

Perform revalidation of AMR* every six months (see Appendix 5 for cartridge-to-cartridge consistency discussion) Assess and approve data; keep records * revalidating reportable range (AMR) and calibration verification are the same activity for the GEM-iQM System

• NIST-traceable PVP may be purchased from IL (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit)

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POC.06400 - .06450 LSV.00700 CHM.10700

System for regular checking of critical operating characteristics and on-going evaluation of records of controls, instrument maintenance and function checks, temperature, etc., for all procedures on all shifts

Review GEM-iQM summary reports according to site’s policies and procedures Maintain records

• GEM-iQM system is maintenance- free • GEM-iQM system automatically and continually assesses and documents critical component function checks and critical analytical components • Operator alerted when system or cartridge operations fall outside performance tolerance specifications

POC.03700 LSV.01100 CHM.10800

Documented system to detect and correct significant clerical and analytical errors, and unusual/ unexpected test results. The system provides for timely correction

Review GEM-iQM summary reports as specified in site’s policies and procedure Maintain records

• GEM-iQM “flags” patient values outside site-approved reference and critical value ranges • All patient results are automatically documented and, with connectivity data are transferred to patients’ record • GEM-iQM automatically detects pre-analytical and analytical errors and, when necessary, immediately initiates and documents corrective actions • GEM-iQM immediately alerts the operator when pre-analytical and analytical errors occur • When automated corrective actions are unsuccessful, affected analyte(s) are automatically disabled

POC.08980 LSV.41570 CHM.34300

Calibration rechecked periodically throughout the day utilizing barometric pressure

Non-applicable • Barometric pressure is not a factor (PC solutions that monitor and maintain the stability of the verified calibration throughout the “life” of the cartridge are in sealed, impermeable bags with no air phase)

LSV.40950 CHM.14150

Calibrators obtained from an outside supplier used as a control is different lot number from that used as a calibrator

Nothing • With each cartridge installation, the sensors are calibrated with a series of two different NIST- traceable solutions • The first step uses internal PC solutions and the second step uses completely different NIST- traceable, external CVP solutions • The internal PC solutions then monitor the analytical process and maintain the stability of the calibration throughout the “life” of the cartridge

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POC. 07300 CHM.13900

Validation of instrument controls for [daily] QC. To initially validate devices using built-in liquid controls, both external and internal controls should be run daily for at least 20 days Once built-in controls are validated, run external QC with each new lot number/cartridge

Perform 20-day validation study as part of the method implementation process Assess external and internal QC data for consistency; approve and document the use of GEM-iQM Maintain records for life of instrument (this is a one time activity performed at implementation)

• NIST-traceable aqueous product may be purchased from IL • IL provides a validation protocol to follow at installation

POC. .09035 LSV.41650 CHM.13900 & .34400

Run appropriate QC daily. Minimum requirements include: • blood gases (pH, pCO2, pO2,) – one level per eight hours of patient testing • glucose, hematocrit, and electrolytes – two levels per 24 hours

Maintain records • GEM-iQM automatically performs and assesses a minimum (with no patient sample analysis) of two levels of PC solution every four hours and a third level (for all analytes except Hct) every 12 hours. This frequency meets or exceeds the mandated QC requirements for all analytes measured • GEM-iQM documents PC solution data, which can be accessed as needed

POC.09090 LSV.41730 CHM.34500

Control materials for pH, pCO2, pO2, represent both high and low values on each day of testing

Nothing • The PC solutions analyzed throughout a 24-hour period represent a range of values

POC.09145 LSV.41810 CHM.34600

One sample of control material for pH, pCO2, pO2 included for each time patient specimens are tested, unless instrument internally calibrates at least once every 30 minutes of use

Nothing • GEM-iQM automatically includes 1-level of PC solution each time patient samples are tested

POC.07456 LSV.40850 CHM.14000

Define or verify a valid QC range of acceptability for each lot of QC material

Test-site director or designee documents approval of GEM Premier 4000’s specified QC (PC) limits based on total allowable error requirements and instrument performance specifications

• PC tolerance limits for each analyte are statistically derived from total allowable error requirements and the GEM Premier 4000’s critical operating specifications (inaccuracy and imprecision)

POC.07428 LSV.41010 CHM.14300

Evaluate QC data daily to detect instrument or process failure

Review and maintain records

• GEM-iQM continuously evaluates PC solution data and initiates corrective actions when PC solution tolerance limits are exceeded or disables the affected analyte(s), if self-correction is not possible • A Delta Chart for each analyte tracks the mean, minimum and maximum values obtained each day for each PC solution

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POC.07484 LSV.41170 CHM.14600

Evidence of documented corrective action when QC results exceed defined tolerance limits

Review and maintain records • GEM-iQM system initiates corrective actions when defined PC solution tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible. All corrective actions are documented and available for review on the analyzer or remotely via GEMweb®

Plus • Operator alerted when PC solution results fall outside tolerance specifications

LSV.41130 CHM.14500

QC statistics (e.g., SD or CV) are calculated at specified intervals to define analytic imprecision

Access GEM-iQM analytical cartridge data according to site’s policies and procedures Maintain records

• PC solution results are evaluated immediately by the instrument software. The statistical information is updated daily, and can be viewed on demand

POC.07512 LSV.41250 CHM.14800

Control specimens tested in the same manner as patient samples

Nothing • GEM-iQM system automatically analyzes the PC solutions in precisely the same manner (follows same fluidic pathway) as patient samples • PC solutions evaluate each step in the testing process

POC. 07540 LSV.41330 CHM.14900

Controls verified for acceptability before reporting results

Review and maintain records • GEM-iQM system continually evaluates PC solution data and notifies the operator when results exceed established tolerance limits (No patient test results are reported when PC data are not acceptable) • GEM-iQM system initiates corrective actions when tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All information is documented and available

GEN.42020 Verified/established and documented analytical accuracy and precision for each test prior to routine implementation

Validate accuracy and precision at initial instrument installation. Test-site director or designee documents approval of the GEM Premier 4000’s accuracy and the IL drift (imprecision) limits Maintain records for the life of the instrument

• Accuracy and precision are verified by analyses of NIST-traceable external CVP and PVP solutions • GEM Premier 4000 is a closed system allowing IL to establish precision limits based on total allowable error requirements and instrument performance specifications • Ongoing, automated analyses of PC solutions continually monitor imprecision

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GEN.42025 Verified/established and documented analytical sensitivity (lower detection limit) for each assay prior to routine implementation.

Test-site director or designee documents acceptance of the analytical sensitivity stated in the GEM Premier 4000 Operator’s Manual (Test sites may conduct additional studies, if desired) Maintain records for the life of the instrument

• Analytical sensitivity has been determined by IL and is documented in the GEM Premier 4000 Operator’s Manual

GEN.42030 Verified/established and documented analytical interferences for each test prior to routine implementation.

Test-site director or designee documents acceptance of the analytical interferences stated in the GEM Premier 4000 Operator’s Manual (Test sites may conduct additional studies, if desired) Maintain records for the life of the instrument

• Known analytical interferences have been evaluated and documented in the GEM Premier 4000 Operator’s Manual • Some interfering substances in patient samples are detected by iQM’s Failure Pattern Recognition software

GEN. 42085 (embraces AMR & CRR) AMR (analytic measurement range) ... Range of values directly measure, without dilution CRR (clinically reportable range)... Allows for specimen dilution, concentration, or other pretreatment

Reportable range verified/established and validated for each analytic procedure prior to routine implementation CRR is not applicable for GEM-iQM System using whole blood

Document the data (See Appendix 5 for discussion of cartridge-to-cartridge consistency) Maintain records

• NIST-traceable PVP may be purchased from IL (five levels for blood gases (excluding pH) , electrolytes, and metabolites; and four levels for pH, tHb and hematocrit)

GEN.42162 (CHM.15300) (POC.04525) (LSV.36920) (literature references or a manufacturer's package insert information may be appropriate)

Reference intervals established [defined] or verified

Test-site director or designee approves the reference ranges stated in the GEM Premier 4000 Operator’s Manual (or from other source) as being appropriate for the test-site’s clientele Document and date approval of data Maintain records

• GEM Premier 4000 Operator’s Manual includes reference ranges

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Appendix 2

Meeting the Clinical Laboratory Improvement Amendments (CLIA 2003) Quality Control (QC) and Performance Specification Requirements

CLIA Standard Number

CLIA Standard Description

What Sites Need to Do to Meet CLIA Standards with the GEM Premier 4000 and iQM (GEM-iQM System)


§493.1200 Each lab must establish and maintain written policies and procedures that implement and monitor quality systems for all phases of the total testing process.

As part of documentation, assemble the QC and QA policies/procedures for the three phases of testing – pre-analytical, analytical and post-analytical

• QC information in the GEM Premier 4000 Operator’s Manual • QC information in GEM Premier 4000 Standard Operating Procedure (SOP) diskette

§493.1250 Monitor and evaluate the overall quality of the analytic systems and correct identified problems.

Review and maintain appropriate records

• GEM-iQM automatically analyzes a minimum of two levels of PC (QC) solutions every four hours and a third level (for all analytes except Hct) every 12 hours. This exceeds the mandated requirements for all analytes measured • PC solution results are evaluated immediately by the instrument software. The statistical information is updated daily, and can be viewed on demand • GEM-iQM continually monitors and maintains the stability of the verified calibration to assure on- going accuracy • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • A Delta Chart for each analyte tracks the mean, minimum and maximum analyte values obtained each day for each PC solution and provides an additional performance check • GEM-iQM immediately alerts the operator when QC tolerance limits are not met • GEM-iQM documents all PC solution results and any corrective actions taken

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What Sites Need to Do to Meet CLIA Standards with the GEM-iQM System


§493.1251 Have a procedure manual describing the processes for testing and reporting patient test results

Assemble a procedure manual that describes the entire testing process including reporting of patient results and test-site specific information

• QC information in the GEM Premier 4000 Operator’s Manual • QC information in GEM Premier 4000 SOP diskette

§493.1252 Follow manufacturer’s instructions in a manner that provides test results within the system’s performance specifications and follow defined criteria for essential conditions (e.g., water quality, temperature, storage of reagents)

Include in procedure manual, the cartridge storage protocol following IL requirements

• All required reagents and solutions are contained in the analytical cartridge and IL supplied. No reagent preparation is required • Cartridge reagents and sensors are validated extensively by GEM- iQM on installation and all must meet specifications prior to patient testing • Each cartridge EEPROM contains cartridge information including expiration date. GEM-iQM does not accept out-dated cartridges • All cartridge information is documented, traceable and available on demand

§493.1253 Establish/verify performance specifications (e.g., demonstrate that the test site can obtain accuracy, precision and reportable-range data comparable to those established by the manufacturer, and verify that the manufacturer’s reference intervals are appropriate to the site’s clientele)

Validate accuracy and precision at initial instrument installation. Test-site director or designee documents approval of the GEM Premier 4000’s accuracy and the IL drift (imprecision) limits Validate the reportable range at initial instrument installation and at least every six months. (See Appendix 5 for discussion of cartridge-to-cartridge consistency) Test-site director or designee approves the reference ranges stated in the GEM Premier 4000 Operator’s Manual (or from other source) as being appropriate for the test-site’s clientele Document and date approval of data Maintain records for life of instrument

• Accuracy and precision are verified by analyses of NIST-traceable external CVP and Performance Verification Product (PVP) solutions (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit) may be purchased from IL • GEM Premier 4000 is a closed system (no operator intervention) allowing IL to establish precision limits based on total allowable error requirements and instrument performance characteristics • On-going, automated analyses of PC solutions continually monitor imprecision • NIST-traceable PVP solutions used (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit) establish the reportable range • GEM Premier 4000 Operator’s Manual includes reference ranges

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§493.1254 Perform and document maintenance and function checks, as defined by the manufacturer

Review GEM-iQM summary reports according to site’s policies and procedures Maintain records

• GEM-iQM system is maintenance- free • GEM-iQM system automatically and continually assesses and documents critical component function checks and critical analytical components • Operator alerted when system or cartridge operations fall outside performance tolerance specifications

§493.1255 §493.1267(a) (special blood gas requirements)

Perform and document calibration and calibration verification procedures, following manufacturer’s instructions. (include barometric pressure and room temperature, as necessary)

Perform calibration verification* every six months to revalidate reportable range (see Appendix 5 for cartridge-to-cartridge consistency discussion) Assess and approve data; keep records *calibration verification and revalidating reportable range are the same activity for the GEM-iQM system

• A new calibration occurs with each cartridge installation on the GEM- iQM System • Cartridge changes do not affect range of reportable results • NIST-traceable PVP may be purchased from IL (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit • Barometric pressure and room temperature are not factors; all solutions are in sealed, impermeable bags with no air phase

§493.1256(a) - (c)(2) Have control procedures that monitor the accuracy and precision of the complete analytical process [and] detect immediate errors due to system failure, adverse environmental conditions, and operator performance. When the stated values of assayed controls are used, the values are for the methodology and instrument, and verified by the laboratory. Results of QC materials must meet the laboratory’s and manufacturer’s test system criteria for acceptability before reporting patient test results. All QC procedures are documented.

Test-site director or designee documents approval of the GEM Premier 4000’s QC/QA approach, which monitors the entire analytical process, and the QC limits, which are based on total allowable error requirements and instrument performance specifications Maintain records

• GEM-iQM System automatically analyzes a minimum of two levels of PC (QC) solutions every four hours and a third level (for all analytes except Hct) every 12 hours • PC solution results are evaluated immediately by the instrument software. The statistical information is updated daily, and can be viewed on demand • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • Delta Charts track mean, minimum and maximum QC values to provide additional performance checks • GEM-iQM system immediately alerts the operator when QC tolerance limits are not met • GEM-iQM system documents all PC solution results and any corrective actions taken

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§493.1256(d) Validation of instrument controls for [daily] QC using Option 1 in the SOM. To initially validate devices using built-in liquid controls, both external and internal controls should be run daily for at least ten days Once built-in controls are validated, run external QC with each new lot number/cartridge

Perform ten-day validation study as part of the method implementation process Assess external and internal QC data for consistency; approve and document the use of GEM-iQM Maintain records for life of instrument (this is a one-time activity performed at implementation)


§493.1267(b) - (special blood gas requirements)

Test one sample of control material every eight hours of testing using a combination of control materials that includes both low and high values on each day of testing Minimum CLIA QC levels & intervals are: • blood gases (pH, pCO2, pO2) – one level per eight hours (include low and high values on each day of testing) • hematocrit, glucose and electrolytes – two levels per 24 hours

Maintain records • GEM-iQM system automatically performs and assesses a minimum (with no patient sample analysis) of two levels of PC solution every four hours and a third level (for all analytes except Hct) every 12 hours. This frequency meets or exceeds the mandated QC requirements for all analytes measured • GEM-iQM system documents PC solution data, which can be accessed as needed

§493.1267(c) - (special blood gas requirements)

Test one sample of control material each time specimens are tested, unless automated instrumentation internally verifies calibration at least every 30 minutes

Nothing • GEM-iQM system automatically includes one level of PC solution each time patient samples are tested

§493.1267(d) - (special blood gas requirements)

Document all control procedures performed in §493.1267(a) through (c)

Review and maintain records • All required information is automatically collected, documented and available on demand

§493.1256(d)(7) Over time, rotate control material testing among all operators who perform the test

Rotate the analyses of external CVP and PVP materials and proficiency testing samples Review and maintain records

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§493.1256(d)(8) Control materials tested in the same manner as patient samples


§493.1256(d)(9) Calibrators and controls are different lot numbers

Nothing • With each cartridge installation, the sensors are calibrated with a series of two different NIST-traceable solutions • The first step uses internal PC solutions and the second step uses completely different NIST- traceable, external CVP solutions • The internal PC solutions then monitor the analytical process and maintain the stability of the calibration throughout the “life” of the cartridge

§493.1256(d)(10), (10)(i), & (10)(ii)

Establish or verify the criteria for acceptability of all control materials. Statistics (e.g., SD or CV) are calculated and available. The lab may use the stated value of a commercially assayed control material, provided the stated value is for the methodology and instrumentation employed by the lab and verified by the lab

Test site director or designee approves the use of GEM Premier 4000’s QC limits, which are based on total allowable error requirements and instrument performance specifications Access GEM-iQM analytical cartridge data according to site’s policies and procedures Maintain records


§493.1256(f) Results of control materials must meet the laboratory’s and, as applicable, the manufacturer’s test system criteria for acceptability before reporting patient test results

Review and maintain records • GEM-iQM system continually evaluates PC solution data and notifies the operator when results exceed established tolerance limits. (No patient test results are reported when PC data are not acceptable) • GEM-iQM system initiates corrective actions when tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All information is documented and available

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§493.1256(g) Laboratory must document all control procedures performed

Review and maintain records

• GEM-iQM system automatically performs and assesses a minimum (with no patient sample analysis) of two levels of PC solution every four hours and a third level (for all analytes except Hct) every 12 hours. This frequency meets or exceeds the mandated QC requirements for all analytes measured • GEM-iQM system initiates corrective actions when tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All information is documented and available

§493.1282 §493.1289

Follow corrective action policies and procedures and document all corrective actions taken Monitor, assess, and, when appropriate, correct identified problems in the analytic systems and document all assessment activities

Review and maintain records • GEM-iQM system initiates corrective actions when defined PC solution tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All corrective actions are documented and available for review including remotely via GEMweb Plus • Operator alerted when PC solution results fall outside tolerance specifications (No patient test results are reported when PC results exceed tolerance limits)

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Appendix 3

Meeting the Joint Commission (JC) 2007 Applicable Quality Control (QC) and Method Performance Specification Requirements

QC.1.65 - QC.1.140; Clinical Chemistry Requirements – QC.6.10 - QC.6.50)

JC Standard Number JC Standard Description What Sites Need to Do to Meet JC Standards with the GEM Premier 4000 and iQM

(GEM-iQM System)


QC.1.65 Have a documented QC program As part of documentation, assemble the QC and QA policies/procedures for the three phases of testing Test-site director or designee documents approval of the GEM Premier 4000’s QC/QA approach, which monitors the entire analytical process, and the QC limits, which are based on total allowable error requirements and instrument performance specifications Maintain records

• QC information in the GEM Premier 4000 Operator’s Manual • QC information in GEM Premier 4000 Standard Operating Procedure (SOP) diskette • GEM-iQM system automatically analyzes a minimum of two levels of PC (QC) solutions every four hours and a third level (for all analytes except Hct) every 12 hours. This exceeds the mandated requirements for all analytes measured • PC solution results are evaluated immediately by the instrument software. The statistical information is calculated daily, and can be viewed on demand • GEM-iQM system continually monitors and maintains the stability of the verified calibration to assure on-going accuracy • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • A Delta Chart for each analyte tracks the mean, minimum and maximum analyte values obtained each day for each PC solution and provides an additional performance check • GEM-iQM system immediately alerts the operator when QC tolerance limits are not met • GEM-iQM system documents all PC solution results and any corrective actions taken

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JC Standard Number JC Standard Description What Sites Need to Do to Meet JC Standards with the GEM-iQM System


QC.1.70 The laboratory’s QC system includes the validation of methods used: • Accuracy • Precision • Reportable Range • Reference Range determined to be appropriate to the population tested.


• Accuracy and precision are verified by analyses of NIST-traceable external CVP and Performance Verification Product (PVP) solutions (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, THb and hematocrit • GEM Premier 4000 is a closed system (no operator intervention) allowing IL to establish precision limits based on total allowable error requirements and instrument performance characteristics • On-going, automated analyses of PC solutions continually monitor imprecision • NIST-traceable PVP solutions used (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, THb and hematocrit) establish the reportable range • GEM Premier 4000 Operator’s Manual includes reference ranges

QC.1.73 The laboratory calibrates instruments and equipment used for patient testing

Nothing • A new calibration occurs with each cartridge installation on the GEM- iQM System

QC.1.75 The laboratory performs calibration verification and recalibration as required

Perform calibration verification* every six months to revalidate reportable range (see Appendix 5 for cartridge-to-cartridge consistency discussion) Assess and approve data; keep records *calibration verification and revalidating reportable range are the same activity for the GEM-iQM system

• A new calibration occurs with each cartridge installation on the GEM- iQM System • Cartridge changes do not affect range of reportable results • NIST-traceable PVP may be purchased from IL (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit)

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QC.1.77 The laboratory validates electronic or internal monitoring systems prior to using them for routine quality control

Perform ten-day validation study as part of the method implementation process Assess external and internal QC data for consistency; approve and document the use of GEM-iQM Maintain records for life of instrument (this is a one time activity performed at implementation)


QC.1.87 The laboratory runs QC in the same manner as patient samples to challenge each step in the testing process


QC.1.100 The laboratory investigates and takes remedial action for deficiencies identified through QC measures

Review and maintain records • GEM-iQM system initiates corrective actions when defined PC solution tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All corrective actions are documented and available for review including remotely via GEMweb Plus • Operator alerted when PC solution results fall outside tolerance specifications (No patient test results are reported when PC results exceed tolerance limits)

QC.1.110 QC results meet the laboratory’s criteria for acceptability before patient results are reported

Review and maintain records • GEM-iQM system continually evaluates PC solution data and notifies the operator when results exceed established tolerance limits. (No patient test results are reported when PC data are not acceptable) • GEM-iQM system initiates corrective actions when tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All information is documented and available

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QC.1.130 QC.1.140

The laboratory follows written guidelines for properly storing, preparing, evaluating, and tracking reagents The laboratory establishes and follows written guidelines for reagent and solution labeling

Include in procedure manual, the cartridge storage protocol following IL requirements and any additional organizational labeling requirements

• All required reagents and solutions are contained in the analytical cartridge supplied and labeled by IL • No reagent preparation is required • Cartridge reagents and sensors are validated extensively by the GEM- iQM system on installation and all must meet specifications prior to patient testing • Each cartridge EEPROM contains cartridge information including expiration date. The GEM-iQM system does not accept out-dated cartridges • All cartridge information is documented, traceable and available on demand

QC.6.10 QC.6.20

The laboratory verifies each procedure in clinical chemistry using controls each day of use Minimum QC levels & intervals are: • hematocrit, glucose and electrolytes – two levels per 24 hours The laboratory verifies the operation of each blood gas testing instrument through the use of control and calibration procedures Minimum QC levels & intervals are: • blood gases (pH, pCO2, pO2) – one level per eight hours (include low and high values on each day of testing)

Test-site director or designee documents approval of the GEM Premier 4000’s QC/QA approach, which monitors the entire analytical process, and the QC limits, which are based on total allowable error requirements and instrument performance specifications Review and maintain records

• A new calibration occurs with each cartridge installation on the GEM- iQM system • GEM-iQM system automatically analyzes a minimum of two levels of PC (QC) solutions every four hours and a third level (for all analytes except Hct every 12 hours • PC solution results are evaluated immediately by the instrument software. The statistical information is updated daily, and can be viewed on demand • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • Delta Charts track mean, minimum and maximum QC values to provide additional performance checks • GEM-iQM system immediately alerts the operator when QC tolerance limits are not met • GEM-iQM system documents all PC solution results and any corrective actions taken

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QC.6.30 The laboratory establishes own QC ranges with valid statistical measurements for each procedure in chemistry



QC.6.40 QC.6.50

The laboratory establishes and makes available to its staff acceptable limits for all standard and reference QC samples, as well as the action to take when results are out-side satisfactory control limits The laboratory establishes test control limits and reportable ranges to provide results with meaningful clinical applications

Test-site director or designee approves the GEM Premier 4000’s specified QC tolerance limits for this closed system. They are based on total allowable error requirements and instrument performance specifications Document approval as providing meaningful clinical applications All corrective actions are instrument initiated Review and maintain records Establish reportable range on method implementation and revalidate every six months

• The QC (PC) range of acceptability for each analyte is statistically derived from total allowable error requirements and instrument performance specifications • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • Delta Charts track mean, minimum and maximum QC values to provide additional performance checks • GEM-iQM system immediately alerts the operator when QC tolerance limits are not met • GEM-iQM system documents all PC solution results and any corrective actions taken

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Appendix 4

Meeting the COLA (June 2007) Criteria for Quality Laboratory Performance Analytic – General Requirements

(COLA criteria are similar to CLIA requirements.

For more information on meeting COLA criteria, refer to Appendix 2)

COLA Standard Number

COLA Standard Description

What Sites Need To Do To Meet COLA Standards with the GEM Premier 4000 and iQM

(GEM-iQM System)


APM 1-19

Procedure manual: Have a procedure manual describing the pre-analytical, analytical, and post-analytical processes (e.g., patient preparation, specimen collection, testing, reporting patient test results, etc.)

Assemble a procedure manual that describes the entire testing process including reporting of patient results and test-site specific information

• QC information in the GEM Premier 4000 Operator’s Manual • QC information in GEM Premier 4000 Standard Operating Procedure (SOP) diskette

MA 1,2,4,17-21,24-26

Maintenance: Follow manufacturer’s instructions in a manner that provides test results within the system’s performance specifications and follow defined criteria for essential conditions (e.g., reagent labeling, storage, and expiration date; instrument function checks, maintenance)

Include in procedure manual, the cartridge storage protocol following IL requirements and any additional organizational, such as, labeling requirements Review and maintain records

• All required reagents and solutions are contained in the labeled analytical cartridge and IL supplied • No reagent preparation is required • Cartridge reagents and sensors are validated extensively by GEM- iQM on installation and all must meet specifications prior to patient testing • Cartridge EEPROM contains cartridge information including expiration date. GEM-iQM does not accept out-dated cartridges • GEM-iQM system is maintenance- free • GEM-iQM system automatically and continually assesses and documents critical component function checks and critical analytical components • All cartridge information is documented, traceable and available on demand

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What Sites Need to Do to Meet COLA Standards with the GEM-iQM System


VER 1-6

Performance Specifications: Prior to patient testing, verify accuracy, precision and reportable patient range and verify that the manufacturer’s reference intervals are appropriate to the site’s clientele


• Accuracy and precision are verified by analyses of NIST-traceable external CVP and Performance Verification Product (PVP) solutions (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit may be purchased from IL • GEM Premier 4000 is a closed system (no operator intervention) allowing IL to establish precision limits based on total allowable error requirements and instrument performance characteristics • On-going, automated analyses of PC solutions continually monitor imprecision • NIST-traceable PVP solutions used (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit establish the reportable range • GEM Premier 4000 Operator’s Manual includes reference ranges

CA 1-9

Calibration: For all non-waived tests and methods, perform calibration and calibration verification at least at the frequency recommended by the manufacturer

Perform calibration verification* every six months to revalidate reportable range (see Appendix 5 for cartridge-to-cartridge consistency discussion) Assess and approve data Maintain records *calibration verification and revalidating reportable range are the same activity for the GEM-iQM System

• With each cartridge installation, the sensors are calibrated with a series of two different NIST- traceable solutions • The first step uses internal PC solutions and the second step uses completely different NIST- traceable, external CVP solutions • The internal PC solutions then monitor the analytical process and maintain the stability of the calibration throughout the “life” of the cartridge • Cartridge changes do not affect range of reportable results • For calibration verification, NIST- traceable PVP may be purchased from IL (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit

22





QC 1-10, 12, 15-16

Quality control: Have control procedures that assure that immediate and ongoing errors can be detected, and thereby produce accurate and reliable results. All control activities must be documented and maintained in accordance with the record keeping requirements in PST 27


• GEM-iQM system automatically analyzes a minimum of two levels of PC (QC) solutions every four hours and a third level (for all analytes except Hct) every 12 hours • PC solution results are evaluated immediately by the instrument software. The statistical information is updated daily, and can be viewed on demand • When PC tolerance limits are exceeded, iQM either rectifies problem(s) or disables affected analyte(s) • Delta Charts track mean, minimum and maximum QC values to provide additional performance checks • GEM-iQM system immediately alerts the operator when QC tolerance limits are not met • GEM-iQM system documents all PC solution results and any corrective actions taken

QC 26

Equivalent QC (EQC) Validation of instrument controls for [daily] QC using option 1. To initially validate devices using built-in liquid controls, both external and internal controls should be run daily for at least 10 days Once built-in controls are validated, run external QC with each new lot number/cartridge

Perform ten-day validation study as part of the method implementation process Assess external and internal QC data for consistency; approve and document the use of GEM-iQM Maintain records for life of instrument (this is a one time activity performed at implementation)


C 1- (special blood gas requirements)

Test one sample of control material each time specimens are tested, unless automated instrumentation internally verifies calibration at least every 30 minutes

Nothing • GEM-iQM System automatically includes one level of PC solution each time patient samples are tested

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C 2- (special blood gas requirements)

Perform and document calibration or calibration verification according to manufacturer’s specifications with the frequency recommended by the manufacturer

Perform calibration verification* every six months to revalidate reportable range (see Appendix 5 for cartridge-to-cartridge consistency discussion) Assess and approve data Maintain records *calibration verification and revalidating reportable range are the same activity for the GEM-iQM system

• With each cartridge installation, the sensors are calibrated with a series of two different NIST- traceable solutions • The first step uses internal PC solutions and the second step uses completely different NIST- traceable, external CVP solutions • The internal PC solutions then monitor the analytical process and maintain the stability of the calibration throughout the “life” of the cartridge • Cartridge changes do not affect range of reportable results • For calibration verification, NIST- traceable PVP may be purchased from IL (five levels for blood gases (excluding pH), electrolytes, and metabolites; and four levels for pH, tHb and hematocrit

C 3,4 - (special blood gas requirements)

Test one sample of control material every eight hours of testing using a combination of control materials that includes both low and high values on each day of testing Minimum QC levels and intervals are: • blood gases (pH, pCO2, pO2) – one level per eight hours (include low and high values on each day of testing) • hematocrit, glucose and electrolytes – two levels per 24 hours

Review and maintain records • GEM-iQM system automatically performs and assesses a minimum (with no patient sample analysis) of two levels of PC solution every four hours and a third level for all analytes except Hct every 12 hours. This frequency meets or exceeds the mandated QC requirements for all analytes measured • GEM-iQM system continually evaluates PC solution data and notifies the operator when results exceed established tolerance limits. (No patient test results are reported when PC data are not acceptable) • GEM-iQM system initiates corrective actions when tolerance limits are exceeded and disables the affected analyte(s) if self-correction is not possible • All information is documented and available

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Appendix 5

How the GEM-iQM system fully meets the CMS (CLIA) Requirement for Calibration and

Calibration Verification As discussed in the Overview Section at the beginning of this paper, the GEM-iQM system introduces a new quality control/quality assurance paradigm, which greatly advances state-of-the-art quality practices. We believe the GEM-iQM system not only meets, but exceeds, the requirements of CMS (CLIA), CAP, JC and COLA. To understand the impact of this new technology on meeting CLIA’s regulatory requirements (and those of the three accrediting agencies), we need to look simultaneously at the specific CLIA regulations and the GEM-iQM system’s operating parameters. §493.1255 (CLIA) Standard: Calibration and calibration verification procedures. (a) Perform and document calibration procedures – (1) Following the manufacturer’s test system instructions, using calibration materials provided or specified, and with at least the frequency recommended by the manufacturer; (2) Using the criteria verified or established by the laboratory as specified in § 493.1253(b)(3)— (i) Using calibration materials appropriate for the test system and, if possible, traceable to a reference method or reference material of known value; and (ii) Including the number, type, and concentration of calibration materials, as well as acceptable limits for and the frequency of calibration; and (3) Whenever calibration verification fails to meet the laboratory’s acceptable limits for calibration verification.

Step 1: When each cartridge is placed on the GEM-iQM system, through the “cartridge-verification” or start-up process, the system automatically completes the first step of the calibration following exactly the manufacturer’s instructions and using the precise, NIST-traceable, materials supplied by the manufacturer. All data are evaluated against internal, manufacturer-set, acceptability-limit criteria. Step 2: When the above (Step 1) “cartridge-verification” or start-up process is successfully completed, the test site completes the calibration process and final accuracy assessment by analyzing a series of liquid, external, NIST-traceable CVP solutions with known values. If each and every acceptance criteria are met in Steps 1 and 2, the GEM-iQM system is ready to analyze patient specimens. If acceptance limits are not met, test channels which fail to meet specifications will not be activated. Typically a failed test channel results in a complete analytical cartridge change.

Note: By accepting the GEM-iQM system, the laboratory director endorses Instrumentation Laboratory’s acceptance limits, including its accuracy and precision specifications.

(b) Perform and document calibration verification procedures— (1) Following the manufacturer’s calibration verification instructions; (2) Using the criteria verified or established by the laboratory under § 493.1253(b)(3)— (i) Including the number, type, and concentration of the materials, as well as acceptable limits for calibration verification; and (ii) Including at least a minimal (or zero) value, a mid-point value, and a maximum value near the upper limit of range to verify the laboratory’s reportable range of test results for the test system; and (3) At least once every six months and whenever any of the following occur: (i) A

25

complete change of reagents for a procedure is introduced, unless the laboratory can demonstrate that changing reagent lot numbers does not affect the range used to report patient test results, and control values are not adversely affected by reagent lot number changes. (ii) There is major preventive maintenance or replacement of critical parts that may influence test performance. (iii) Control materials reflect an unusual trend or shift, or are outside of the laboratory’s acceptable limits, and other means of assessing and correcting unacceptable control values fail to identify and correct the problem. (iv) The laboratory’s established schedule for verifying the reportable range for patient test results requires more frequent calibration verification.

(b), (b)(1), (b)(2), (b)(2)(i) and(ii) are fully met as noted in the discussion on each cartridge-verification on installation with analyzing two distinct NIST-traceable materials and with the initial establishment of reportable range using four- and five-level PVP solutions as part of the verification of performance specifications prior to implementing the GEM-iQM system into routine use. (b)(3), (b)(3)(i) Each new cartridge on the GEM-iQM system is extensively verified (Steps 1 and 2, above) on installation. All critical analytical component tolerances must be met for successful installation and checked continually throughout cartridge use-life with PC solutions. If any of these control results were adversely affected (CLIA terminology), the cartridge would be rejected. Hence, for each cartridge change that successfully completes the installation verification process, the system demonstrates that the “control values are not adversely affected.” (b)(3)(ii) There is no maintenance or critical parts. Cartridge-to-cartridge consistency is demonstrated further with CAP proficiency testing (PT) survey data (see discussion in the section below). Successful cartridge installation establishes that the GEM-iQM system is fully functional and meets manufacturer’s acceptance limits, hence the assertion that cartridge changes do not “influence test performance.” (b)(3)(iii) The on-going assessments by PC solutions detect and assess any unusual trend or shift or outside acceptable (control) tolerance limits situations. If the GEM-iQM system does not correct the problem, the affected test channel is shut down. (b)(3)(iv) When the test site director accepts the GEM-iQM system, the test site accepts the Instrumentation Laboratory six-month schedule for reverifying reportable range (calibration verification) based on demonstrated cartridge-to-cartridge consistency.

GEM Cartridge-to-Cartridge (C-C) Consistency Demonstration with GEM Premier 3000 Data (currently accumulating GEM Premier 4000 data) College of American Pathologists (CAP) Proficiency Testing Survey data are reported in Table 1 for the GEM Premier 3000. Table 1 (2006) shows the CAP PT results for 15 specimens (three PT events per year, each event consists of five specimens). The mean, SD and CV values for each of the nine analytes are reported in the first three rows for each of the three annual PT events. The right most columns (“Avg Variability”) show the average SDs and CVs for the five specimens. The numbers of PT results reported are from up to 969 different cartridges in concurrent use at the time of the surveys. These inter-laboratory measurements reflect cartridge variation (lot numbers), operator introduced artifacts, testing environments, and PT sample handling. The third column in the bottom rows of the Table aggregates the inter-laboratory PT data (avg SDs/avg CVs) for the entire (15 PT specimens) year. These parameters – CVs and SDs –

26

are directly comparable to the GEM Premier 3000’s performance claims of within run [WR], (i.e., intra-cartridge) precision (Column 4) derived from back-to-back analysis of a single specimen on a single cartridge. Column 5 in the bottom rows summarizes the inter-laboratory (PT data) versus intra-laboratory (IL) data comparisons. Intuitively, the “between” inter- cartridge variance shown with CAP PT Survey data is expected to be greater than the average within-run, intra-cartridge variances claimed by the manufacturer. Table 1 clearly shows that this is NOT the case. The CAP PT survey data and intra-cartridge performance are, within statistical limits, essentially the same for all analytes! This is proof of cartridge-to-cartridge consistency.

27

Table 1. Cartridge-to-Cartridge (C-C) Variability Observed in CAP Proficiency Testing 2006

Event AQ-A 2006 Specimen AQ-01 Specimen AQ-02 Specimen AQ-03 Specimen AQ-04 Specimen AQ-05 Avg Variability

Test Labs Mean SD CV Labs Mean SD CV Labs Mean SD CV Labs Mean SD CV Labs Mean SD CV Avg SD Avg CV

pH 884 7.165 0.008 884 77.625 0.006 883 7.09 0.009 884 7.479 0.005 885 7.491 0.005 0.0066

pCO2

875 46.7 1.0 2.20 878 18.2 0.7 3.60 868 63.1 1.50 2.40 876 21.4 0.7 3.10 876 19 0.7 3.80 0.92 3.02

pO2

716 152.2 4.3 2.80 734 146.6 4.3 2.90 726 92.7 2.60 2.80 737 87.1 2.3 2.70 733 115.5 3.2 2.70 3.34 2.78

K+

406 2.22 0.05 2.50 404 5.07 0.06 1.20 407 4.30 0.06 1.30 401 6.25 0.06 1.00 404 5.70 0.07 1.20 0.06 1.44

Na+

389 122 0.8 0.70 391 159.3 1.2 0.80 392 132.3 1.00 0.70 389 156.1 1.10 0.70 389 151.8 1.1 0.70 1.04 0.72

Ca++

424 1.476 0.014 1.70 412 1.367 0.028 2.10 0.021 1.90

Glucose 188 45.2 2.3 5.10 187 302.9 8.4 2.80 186 70.4 3.00 4.20 188 43.6 2.4 5.50 188 287.8 8.3 2.90 4.88 4.10

Lactate 184 0.79 0.04 5.40 185 2.27 0.11 4.90 0.075 5.15

Hematocrit 357 23.6 0.9 3.90 356 32.5 0.9 2.70 356 41.9 0.80 2.00 360 29.4 1.0 3.30 356 20.1 0.9 4.40 0.9 3.26

Event AQ-B 2006 Specimen AQ-06 Specimen AQ-07 Specimen AQ-08 Specimen AQ-09 Specimen AQ-10 Avg Variability


pH 903 7.103 0.008 900 7.346 0.006 906 7.157 0.009 899 7.620 0.005 905 7.520 0.005 0.0066

pCO2

892 58.7 1.4 2.30 890 36,4 0.7 1.90 891 68.4 1.70 2.40 897 17.8 0.6 3.40 901 18.6 0.7 3.80 1.02 2.76

pO2

753 116.8 3.7 3.10 762 73.6 2.3 3.20 774 56.5 2.30 4.10 761 144.9 4.3 3.00 759 116.0 3.7 3.20 3.26 3.32

K+

405 3.15 0.06 1.90 403 4.76 0.06 1.20 402 2.70 0.04 1.50 400 5.03 0.06 1.20 400 5.50 0.07 1.20 0.058 1.40

Na+

391 133.8 1.1 0.80 390 139.6 1.1 0.80 393 124.9 1.00 0.80 388 159.4 1.40 0.90 386 154.5 1.3 0.80 1.18 0.82

Ca++

417 0.904 0.02 2.20 417 0.798 0.017 2.10 0.0185 2.15

Glucose 198 255.5 6.4 2.50 197 41.6 2.3 5.50 200 69.4 2.90 4.10 199 301.0 8.7 2.90 199 275.4 7.6 2.70 5.58 3.54

Lactate 185 2.82 0.10 3.60 187 5.59 0.19 3.40 0.145 3.50

Hematocrit 358 40.9 0.8 2.00 358 34.6 0.9 2.50 357 20.4 0.90 4.50 359 29.8 0.9 2.90 358 23.9 1.0 4.20 0.9 3.22

Event AQ-C 2006 Specimen AQ-11 Specimen AQ-12 Specimen AQ-13 Specimen AQ-14 Specimen AQ-15 Avg Variability


pH 969 7.577 0.006 971 7.14 0.007 970 7.349 0.005 971 7.087 0.007 968 7.343 0.005 0.006

pCO2

968 15.9 0.7 4.40 959 61.2 1.4 2.40 961 34.9 0.60 1.70 965 63.1 1.3 2.10 963 36.1 0.6 1.80 0.92 2.48

pO2

813 72.9 2.6 3.50 804 117 3.4 2.90 814 115.4 3.20 2.80 812 93.0 2.4 2.60 814 72.3 2.2 3.10 2.76 2.98

K+

452 4.88 0.06 1.30 449 3.13 0.05 1.50 458 3.78 0.04 1.20 449 7.46 0.07 1.00 454 4.71 0.04 0.80 0.052 1.16

Na+

444 148.3 1.3 0.90 440 133.2 1.0 0.70 443 141.9 1.00 0.70 439 129,4 1 0.70 437 137.1 0.8 0.60 1.02 0.72

Ca++

462 0.681 0.013 1.80 462 0.916 0.018 1.90 0.0155 1.85

Glucose 239 321.5 10.3 3.20 239 120.1 3.9 3.20 239 173.6 5.10 3.00 241 94.9 3.4 3.60 239 42.0 2.3 5.50 5 3.70

Lactate 213 2.25 0.10 4.50 212 1.70 0.07 4.40 0.085 4.45

Hematocrit 396 25.5 1.0 3.80 396 42.0 0.9 2.10 397 20.1 1.00 4.90 396 32.4 0.9 2.80 397 53.4 0.9 1.70 0.94 3.06

Summary 2006 Event AQ-A Event AQ-B Event AQ-C Average C-C 2006 GEM Caim Within-Run Precision Comparison C-C & WR Precision

Test Avg SD Avg CV Avg SD Avg CV Avg SD Avg CV Avg SD Avg CV N Lo Hi Avg

pH 0.0066 0.007 0.006 0.0064 49-56 0.006 0.012 0.01 C-C avg lower than avg WR

pCO2

0.92 3.02 1.02 2.76 0.92 2.48 0.95 2.75 42-56 1.25 2.97 2.78 C-C avg same as avg WR

pO2

3.34 2.78 3.26 3.32 2.76 2.98 3.12 3.03 49-56 1.43 5.63 1.97 C-C avg within range obs WR

K+

0.06 1.44 0.058 1.40 0.052 1.16 0.057 1.33 54-56 0.79 3.53 2.12 C-C avg lower than avg WR

Na+

1.04 0.72 1.18 0.82 1.02 0.72 1.08 0.75 53-56 0.46 1.16 0.76 C-C avg same as avg WR

Ca++

0.021 1.90 0.019 2.15 0.0155 1.85 0.0183 1.97 26-56 1.28 3.75 2.29 C-C avg lower than avg WR

Glucose 4.88 4.10 5.58 3.54 5 3.70 5.1533 3.78 84-84 3.10 5.00 4.17 C-C avg lower than avg WR

Lactate 0.075 5.15 0.145 3.50 0.085 4.45 0.1017 4.37 33-36 1.35 6.26 2.82 C-C avg within range obs WR

Hematocrit 0.9 3.26 0.9 3.22 0.94 3.06 0.9133 3.18 47-55 1.42 3.64 2.49 C-C avg within range obs WR

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