For In Vitro Diagnostic Use. Rx Only. ANNUAL REVIEW Reviewed by Date Reviewed by Date

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1 SYNCHRON System(s) Chemistry Information Sheet 2017 Beckman Coulter, Inc. All rights reserved. IBCT Total Iron Binding Capacity For In Vitro Diagnostic Use Rx Only ANNUAL REVIEW Reviewed by Date Reviewed by Date PRINCIPLE INTENDED USE IBCT reagent, when used in conjunction with DxC 600/800 System(s) and SYNCHRON Systems FE/IBCT Calibrator Kit, is intended for the quantitative determination of total iron binding capacity in human serum or heparinized (sodium) plasma. CLINICAL SIGNIFICANCE Alterations in iron and total iron binding capacity levels result from changes in iron intake, absorption, storage, and release mechanisms. Such changes are indicative of a wide range of dysfunctions including anemias, nephrosis, cirrhosis and hepatitis. Both iron and total iron binding capacity measurements are important for definitive diagnosis because they are interrelated. Tietz has presented a summary of these relationships and the patterns of iron/total iron-binding capacity associated with various disease states. 1 METHODOLOGY Transferrin in serum or heparinized plasma is completely saturated by adding excess ferric ion in the form of ferric chloride. Any iron not bound to transferrin is absorbed by aluminum oxide in the column. Iron-bound transferrin in the supernatant is measured by the IBCT reagent. IBCT reagent is used to measure the iron concentration by a timed-endpoint method. In the reaction, iron is released from transferrin by acetic acid and is reduced to the ferrous state by hydroxylamine and thioglycolate. The ferrous ion is immediately complexed with the FerroZine Iron Reagent. The SYNCHRON System(s) automatically proportions the appropriate sample and reagent volumes into a cuvette. The ratio used is one part sample to 8 parts reagent. The System monitors the change in absorbance at 560 nanometers. This change in absorbance is directly proportional to the concentration of iron bound to transferrin in the sample and is used by the System to calculate and express the total iron-binding capacity. Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 1 of 14

2 CHEMICAL REACTION SCHEME Sample preparation: Ferrozine reaction: SPECIMEN TYPE OF SPECIMEN Biological fluid samples should be collected in the same manner routinely used for any laboratory test. 2 Freshly drawn serum or heparinized-plasma is the preferred specimen. Whole blood, urine, and non-heparinized plasma are not recommended for use as a sample. SPECIMEN STORAGE AND STABILITY 1. Tubes of blood are to be kept closed at all times and in a vertical position. It is recommended that the serum or plasma be physically separated from contact with cells within two hours from the time of collection Separated serum or plasma should not remain at room temperature longer than 8 hours. If assays are not completed within 8 hours, the separated sample should be stored at +2 C to +8 C. If assays are not completed within 24 hours, plasma samples should be recentrifuged and separated from precipitate before testing. If assays are not completed within 48 hours, or the separated sample is to be stored beyond 48 hours, samples should be frozen at -15 C to -20 C. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed Effluent may be stored at +2 C to +8 C up to 8 hours. Additional specimen storage and stability conditions as designated by this laboratory: SAMPLE PREPARATION 1. Pipette 0.50 ml of sample to be analyzed into an appropriately labeled test tube. 2. Add 1.00 ml of Iron Saturating Solution into each test tube. 3. Vortex thoroughly for 2-3 seconds and incubate at room temperature for 5-7 minutes. 4. Label one column per sample and place the column, with the attached cup, in an upright position in a test tube rack. IBCT English Chemistry Information Sheet A18504 AU Page 2 of 14 OCTOBER 2017

3 NOTICE Discard any column that exhibits: Column packing (alumina powder and filters) which does not appear level and/or intact. Excessive alumina powder within the column sample cup. 5. Pour the sample mixture into the labeled column. 6. Allow the entire mixture to pass through the column (approximately 8 minutes) and collect effluent in the cup. 7. Remove and discard column. 8. Mix gently and then transfer an aliquot of the effluent to a SYNCHRON sample cup for IBCT determination. 9. Load cups into racks and place on instrument or store cups covered at +2 C to +8 C for up to eight hours. NOTICE Do not use the effluent as a sample for any other chemistry assay. The SYNCHRON System(s) account for the sample dilution when reporting the total iron-binding capacity value. A factor is included in the database to account for the three-fold dilution of the specimen with saturation reagent. SAMPLE VOLUME The optimum volume, when using a 0.5 ml sample cup, is 0.3 ml of sample. For optimum primary sample tube volumes and minimum volumes, refer to the Primary Tube Sample Template for your system. CRITERIA FOR UNACCEPTABLE SPECIMENS Refer to the PROCEDURAL NOTES section of this chemistry information sheet for information on unacceptable specimens. Criteria for sample rejection as designated by this laboratory: PATIENT PREPARATION Special instructions for patient preparation as designated by this laboratory: Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 3 of 14

4 SPECIMEN HANDLING Special instructions for specimen handling as designated by this laboratory: REAGENTS CONTENTS Each kit contains the following items: Item No Two IBCT Reagent Cartridges (2 x 100 tests) REF Two 60 ml bottles Iron Saturating Solution Alumina Columns (20 pouches x 5 columns) VOLUMES PER TEST Sample Volume 25 µl Total Reagent Volume 210 µl Cartridge Volumes A 200 µl B C 10 µl REACTIVE INGREDIENTS IBCT English Chemistry Information Sheet A18504 AU Page 4 of 14 OCTOBER 2017

5 REAGENT CONSTITUENTS TOTAL IRON-BINDING CAPACITY REAGENT: FerroZine a 0.4 mmol/l Acetic acid 0.5 M Hydroxylamine hydrochloride 0.3 M Thioglycolic acid 22.3 mmol/l IRON SATURATING SOLUTION: Ferric Chloride 5 mg/l ALUMINA COLUMNS: Aluminum Oxide 300 mg Also non-reactive chemicals necessary for optimal system performance. a Registered trademarks are the property of their respective owners. GHS HAZARD CLASSIFICATION Not classified as hazardous Safety Data Sheet is available at techdocs.beckmancoulter.com MATERIALS NEEDED BUT NOT SUPPLIED WITH REAGENT KIT SYNCHRON Systems FE/IBCT Calibrator Kit At least two levels of control material Saline REAGENT PREPARATION No preparation is required. ACCEPTABLE REAGENT PERFORMANCE The acceptability of a reagent is determined by successful calibration and by ensuring that quality control results are within your facility's acceptance criteria. REAGENT STORAGE AND STABILITY IBCT reagent when stored unopened at +2 C to +8 C, will obtain the shelf-life indicated on the cartridge label. Once opened, the reagent is stable for 60 days at +2 C to +8 C unless the expiration date is exceeded. DO NOT FREEZE. Reagent storage location: Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 5 of 14

6 CALIBRATION CALIBRATOR REQUIRED SYNCHRON Systems FE/IBCT Calibrator Kit CALIBRATOR PREPARATION No preparation is required. NOTICE Use the calibrators as provided. Do not pretreat the calibrator solutions as described in the Sample Preparation section. CALIBRATOR STORAGE AND STABILITY SYNCHRON Systems FE/IBCT Calibrator Kit is stable until the expiration date printed on the calibrator bottles if stored capped in the original container at room temperature. DO NOT FREEZE. Calibrator storage location: CALIBRATION INFORMATION 1. The system must have a valid calibration in memory before controls or patient samples can be run. 2. Under typical operating conditions the IBCT reagent cartridge must be calibrated every 14 days and also with certain parts replacements or maintenance procedures, as defined in the UniCel DxC 600/800 System Instructions For Use (IFU) manual. 3. For detailed calibration instructions, refer to the UniCel DxC 600/800 System Instructions For Use (IFU) manual. 4. The system will automatically perform checks on the calibration and produce data at the end of calibration. In the event of a failed calibration, the data will be printed with error codes and the system will alert the operator of the failure. For information on error codes, refer to the UniCel DxC 600/800 System Instructions For Use (IFU) manual. TRACEABILITY For Traceability information refer to the Calibrator instructions for use. QUALITY CONTROL At least two levels of control material should be analyzed daily. In addition, these controls should be run with each new calibration, with each new reagent cartridge, and after specific maintenance or troubleshooting procedures as detailed in the appropriate system manual. More frequent use of controls or the use of additional controls is left to the discretion of the user based on good laboratory practices or laboratory accreditation requirements and applicable laws. The following controls should be prepared and used in accordance with the package inserts. Discrepant quality control results should be evaluated by your facility. IBCT English Chemistry Information Sheet A18504 AU Page 6 of 14 OCTOBER 2017

7 Table 1.0 Quality Control Material CONTROL NAME SAMPLE TYPE STORAGE TESTING PROCEDURE(S) 1. If necessary, load the reagent onto the system. 2. After reagent load is completed, calibration may be required. 3. Program samples and controls for analysis. 4. After loading samples and controls onto the system, follow the protocols for system operations. For detailed testing procedures, refer to the UniCel DxC 600/800 System Instructions For Use (IFU) manual. CALCULATIONS The SYNCHRON System(s) performs all calculations internally to produce the final reported result. The system will calculate the final result for sample dilutions made by the operator when the dilution factor is entered into the system during sample programming. REPORTING RESULTS Equivalency between the SYNCHRON LX and UniCel DxC 600/800 Systems has been established. Chemistry results between these systems are in agreement and data from representative systems may be shown. REFERENCE INTERVALS Each laboratory should establish its own reference intervals based upon its patient population. The following reference intervals were taken from literature and a study performed on SYNCHRON CX Systems. 4 Table 2.0 Reference intervals a a INTERVALS SAMPLE TYPE CONVENTIONAL UNITS S. I. UNITS Literature Serum (Infants) µg/dl µmol/l Serum (Children) µg/dl µmol/l Serum (Adults) µg/dl µmol/l SYNCHRON Serum (Adults) µg/dl µmol/l Data shown was collected using SYNCHRON CX Systems. Equivalency between SYNCHRON LX Systems has been established by Deming regression analysis to SYNCHRON CX Systems. Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 7 of 14

8 INTERVALS SAMPLE TYPE CONVENTIONAL UNITS S. I. UNITS Laboratory Refer to References (5,6,7) for guidelines on establishing laboratory-specific reference intervals. Additional reporting information as designated by this laboratory: PROCEDURAL NOTES ANTICOAGULANT TEST RESULTS 1. If plasma is the sample of choice, the following anticoagulants were found to be compatible with this method, based on a study of 25 healthy volunteers: Table 3.0 Acceptable Anticoagulants a ANTICOAGULANT LEVEL TESTED FOR IN VITRO INTERFERENCE AVERAGE PLASMA-SERUM BIAS (µg/dl) Sodium Heparin 14 Units/mL NSI b a Data shown was collected using SYNCHRON CX Systems. Equivalency between SYNCHRON LX Systems has been established by Deming regression analysis to SYNCHRON CX Systems. b NSI = No Significant Interference (within ± 20 µg/dl or ± 8%). 2. The following anticoagulants were found to be incompatible based on the same study: Table 4.0 Incompatible Anticoagulants a a b ANTICOAGULANT LEVEL TESTED FOR IN VITRO INTERFERENCE PLASMA-SERUM BIAS (µg/dl) b Ammonium Heparin 14 Units/mL - 56 Lithium Heparin 14 Units/mL - 64 Data shown was collected using SYNCHRON CX Systems. Equivalency between SYNCHRON LX Systems has been established by Deming regression analysis to SYNCHRON CX Systems. Bias is based on worst case instead of average. Plus (+) or minus (-) signs in this column signify positive or negative bias. LIMITATIONS 1. EDTA, sodium citrate, and potassium oxalate are known to interfere with this method. 2. Use disposable labware whenever possible. Rinse glassware with 0.1N HCl before use. 3. Ingestion of oral contraceptives will elevate iron and/or total iron binding capacity values Iron-dextran administration can cause elevations in total iron-binding capacity with this methodology. 5. The SYNCHRON Systems account for the sample dilution when reporting the total iron-binding capacity value. Since the calibrator is not diluted, it will not recover its setpoint value when run as a sample. IBCT English Chemistry Information Sheet A18504 AU Page 8 of 14 OCTOBER 2017

9 INTERFERENCES 1. The following substances were tested for interference with this methodology: Table 5.0 Interferences a SUBSTANCE SOURCE LEVEL OBSERVED EFFECT b Bilirubin Human (total) 27 mg/dl NSI c Human (conjugated) 14 mg/dl NSI Lipemia Human 4+ NSI Copper NA d 450 µg/dl NSI Magnesium NA 12 mg/dl NSI a Data shown was collected using SYNCHRON CX Systems. Equivalency between SYNCHRON LX Systems has been established by Deming regression analysis to SYNCHRON CX Systems. b Plus (+) or minus (-) signs in this column signify positive or negative interference. c NSI = No Significant Interference (within ± 20 µg/dl or ± 8%). d NA = Not applicable. 2. Refer to References (9,10,11) for other interferences caused by drugs, disease and preanalytical variables. 3. Samples showing evidence of hemolysis should not be used. Hemolysis may cause falsely elevated results. PERFORMANCE CHARACTERISTICS ANALYTIC RANGE The SYNCHRON System(s) method for the determination of this analyte provides the following analytical ranges: Table 6.0 Analytical Range SAMPLE TYPE CONVENTIONAL UNITS S.I. UNITS Serum µg/dl µmol/l For samples with concentrations exceeding the high end of the analytical range: 1. Dilute the effluent with saline. 2. Reanalyze (see Calculations section of this chemistry information sheet). REPORTABLE RANGE (AS DETERMINED ON SITE): Table 7.0 Reportable Range SAMPLE TYPE CONVENTIONAL UNITS S.I. UNITS SENSITIVITY Sensitivity is defined as the lowest measurable concentration which can be distinguished from zero with 95% confidence. Sensitivity for IBCT determination is 10 µg/dl (1.8 µmol/l). Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 9 of 14

10 EQUIVALENCY Equivalency was assessed by Deming regression analysis of patient samples to accepted clinical methods. Serum or Heparinized Plasma (in the range of 14 to 966 µg/dl): Y (SYNCHRON LX Systems) = 0.980X N = 79 MEAN (SYNCHRON LX Systems) = MEAN (SYNCHRON CX7 DELTA) = CORRELATION COEFFICIENT (r) = Refer to References (12) for guidelines on performing equivalency testing. PRECISION A properly operating SYNCHRON System(s) should exhibit precision values less than or equal to the following: Table 8.0 Precision Values 1 SD CHANGEOVER VALUE TYPE OF a PRECISION SAMPLE TYPE µg/dl µmol/l µg/dl µmol/l % CV Within-run Serum/Plasma Total Serum/Plasma a When the mean of the test precision data is less than or equal to the changeover value, compare the test SD to the SD guideline given above to determine the acceptability of the precision testing. When the mean of the test precision data is greater than the changeover value, compare the test % CV to the guideline given above to determine acceptability. Changeover value = (SD guideline/cv guideline) x 100. Comparative performance data for a SYNCHRON LX System evaluated using the NCCLS Proposed Guideline EP5-T2 appears in the table below. 13 Each laboratory should characterize their own instrument performance for comparison purposes. Table 9.0 NCCLS EP5-T2 Precision Estimate Method a TYPE OF IMPRECISION Within-run Total SAMPLE TYPE No. Systems No. Data Points a EP5-T2 Calculated Test Mean Point Estimates Value (µg/dl) SD %CV Serum Control Serum Control Serum Control Serum Control Serum Control Serum Control The point estimate is based on the data from one system, run for twenty days, two runs per day, two observations per run on an instrument operated and maintained according to the manufacturer`s instructions. IBCT English Chemistry Information Sheet A18504 AU Page 10 of 14 OCTOBER 2017

11 NOTICE These degrees of precision and equivalency were obtained in typical testing procedures on a SYNCHRON LX System and are not intended to represent the performance specifications for this reagent. ADDITIONAL INFORMATION For more detailed information on UniCel DxC Systems, refer to the appropriate system manual. Beckman Coulter, the stylized logo, and the Beckman Coulter product and service marks mentioned herein are trademarks or registered trademarks of Beckman Coulter, Inc. in the United States and other countries. SHIPPING DAMAGE If damaged product is received, notify your Beckman Coulter Clinical Support Center. REVISION HISTORY Revision AG Updated corporate address; removed insert reference from content description and removed EDTA as an Acceptable Anticoagulant claim. Revision AH Revised Sample Preparation and Reagent Contents sections. Revision AJ Added Revision History Revision AK Removed the interference claim for hemolysis and added a limitation statement. Revision AL Added new language requirement: Czech, and Korean. Revision AM Removed references to CX and LX systems as they are discontinued effective 12/2013. Added Beckman Coulter trademark statement and disclaimer. Revision AN Added GHS Classification information Revision AP Added REF number: Revision AR Added new language requirement: Romanian Revision AT Updates to comply with requirements per Beckman Coulter Global Labeling Policy. Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 11 of 14

12 Revision AU Additional changes to comply with requirements per Beckman Coulter Global Labeling Policy. IBCT English Chemistry Information Sheet A18504 AU Page 12 of 14 OCTOBER 2017

13 SYMBOLS KEY Table 10.0 Catalogue Number Contents Manufacturer Batch code CE Mark Authorized Representative in the European Community DANGER IBCT Iron Saturating Solution In Vitro Diagnostic Temperature limit Expiration Date Safety Data Sheet Consult Instructions for Use Date of Manufacture Do not reuse IBCT Columns Made in USA of US and Foreign Components FOOTNOTES Registered trademarks are the property of their respective owners. Chemistry Information Sheet A18504 AU English IBCT OCTOBER 2017 Page 13 of 14

14 REFERENCES 1. Tietz, N. W., Textbook of Clinical Chemistry, W. B. Saunders Company, Philadelphia, PA (1986). 2. Tietz, N. W., "Specimen Collection and Processing; Sources of Biological Variation", Textbook of Clinical Chemistry, 5th Edition, W. B. Saunders, Philadelphia, PA (2005). 3. National Committee for Clinical Laboratory Standards, Procedures for the Handling and Processing of Blood Specimens Approved Guideline, NCCLS publication H18-A, Villanova, PA (1990). 4. Bakerman, S., ABC`s of Interpretive Laboratory Data, 3rd Edition, Interpretive Laboratory Data, Inc., Greenville, NC (1994). 5. National Committee for Clinical Laboratory Standards, How to Define, Determine, and Utilize Reference Intervals in the Clinical Laboratory Approved Guideline, NCCLS publication C28-A, Villanova, PA (1995). 6. Tietz, N. W., ed., Fundamentals of Clinical Chemistry, 6th Edition, W. B. Saunders, Philadelphia, PA (2007). 7. Henry, J. B., Clinical Diagnosis and Management by Laboratory Methods, 22nd Edition, W. B. Saunders Company, Philadelphia, PA (2006). 8. Weissman, M., Pileggi, V. J., Clinical Chemistry: Principles and Techniques, Harper and Row Publishers, Hagerstown, MD (1974). 9. Young, D. S., Effects of Drugs on Clinical Laboratory Tests, 5th Edition, AACC Press, Washington, D. C. (2000). 10. Friedman, R. B., Young, D. S.,Effects of Disease on Clinical Laboratory Tests, 4th Edition, AACC Press, Washington, D.C. (2001). 11. Young, D. S., Effects of Preanalytical Variables on Clinical Laboratory Tests, 3rd Edition, AACC Press, Washington, D. C. (2007). 12. National Committee for Clinical Laboratory Standards, Method Comparison and Bias Estimation Using Patient Samples Approved Guideline, NCCLS publication EP9-A, Villanova, PA (1995). 13. National Committee for Clinical Laboratory Standards, Precision Performance of Clinical Chemistry Devices Tentative Guideline, 2nd Edition, NCCLS publication EP5-T2, Villanova, PA (1992). Beckman Coulter Eurocenter S.A., 22, rue Juste-Olivier. Case Postale 1044, CH Nyon 1, Switzerland Tel: +41 (0) Beckman Coulter, Inc., 250 S. Kraemer Blvd., Brea, CA U.S.A. IBCT English Chemistry Information Sheet A18504 AU Page 14 of 14 OCTOBER 2017