TINA-QUANT FERRITIN GEN. 4

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY A. 510(k) Number: k100538 B. Purpose for Submission: Modifications to reagent formulation C. Measurand: Ferritin D. Type of Test: Quantitative, immunoturbidimetric E. Applicant: Roche Diagnostics F. Proprietary and Established Names: Tina-Quant Ferritin Gen. 4 G. Regulatory Information: 1. Regulation section: 21 CFR § 866.5340 Ferritin Immunological test system 2. Classification: Class II 3. Product code: DBF – Ferritin, antigen, antiserum, control 4. Panel: Immunology (82) H. Intended Use: 1. Intended use(s): Tina-Quant Ferritin assay is an *in vitro* immunoturbidimetric test for the quantitative determination of ferritin in human serum and plasma using Roche/Hitachi clinical chemistry analyzers. 2. Indication(s) for use: Measurements obtained by this device are used in the aid of diagnosis of diseases affecting iron metabolism in conjunction with other clinical and laboratory findings. 3. Special conditions for use statement(s): Prescription use only. 4. Special instrument requirements: Roche/Hitachi 902/912/917/Modular P analyzers: ACN 692 I. Device Description: The Tina-Quant Ferritin Gen. 4 assay consists of R1: Tris Buffer pH =7.5, stabilizing polyclonal antibodies and preservative; and R3: latex particles coated with anti-human ferritin antibodies (rabbit), stabilizers and preservative. The recommended calibrator is C.f.a.s. Proteins cleared in k080607. The two controls are Precinorm Protein and Precipath Protein which were cleared in k012371. J. Substantial Equivalence Information: 1. Predicate device name(s): Tina-Quant Ferritin {1} 2. Predicate 510(k) number(s): k964282 3. Comparison with predicate: | Similarities | | | | --- | --- | --- | | Item | Device | Predicate | | | Tina-Quant Ferritin Gen. 4 | Tina-Quant Ferritin | | Intended Use | In vitro test for the quantitative determination of ferritin in human serum and plasma on Roche automated clinical chemistry analyzers. | Same | | Assay Principle | Immunoturbidimetric | Same | | Labeled Instrument Platform | Roche/Hitachi | Roche/Hitachi | | Calibrator | C. f. a. s. Proteins | Same | | Controls | Precinorm and Precipath Protein | Same | | Calibration Frequency | For every lot change and as required following quality control procedures | Same | | Primary Antibody | Rabbit anti-human ferritin | Same | | Analytical Specificity | The antibodies are specific for ferritin from human liver and recognize ferritin from human spleen. The antibodies show no cross reactivity to the human ferritin H subunit. | Same | | Differences | | | | --- | --- | --- | | Item | Device | Predicate | | | Tina-Quant Ferritin Gen. 4 | Tina-Quant Ferritin | | Sample Type | Serum and plasma (Li-heparin, and EDTA) | Serum and plasma (heparinized, citrated, and EDTA) | | Reagent Composition | R1: - Tris buffer (increased conc.) - pH 7.5, - Stabilizing antibodies (decreased conc.) | R1: - Tris Buffer - pH 8.2 - Stabilizing antibodies | | | R3: - latex particles (decreased conc.) coated with anti-human ferritin antibodies | R2: - latex particles coated with anti-human ferritin antibodies | {2} | Differences | | | | --- | --- | --- | | Item | Device | Predicate | | Reagent Stability | Unopened: 24 months at 2-8°C Opened (on-board): 84 days | Unopened: 15 months at 2-8°C Opened (on-board): 28 days | | Measuring Range | Roche/Hitachi 902: 5-800 ng/mL | Roche/Hitachi 902: 5-400 ng/mL | | | Roche/Hitachi 912/917/Modular P: 5-1000 ng/mL | Roche/Hitachi 912/917/Modular P: 15-800 ng/mL | | Analytical Sensitivity | LoB: 3 ng/mL LoD: 5 ng/mL | LoD: 15 ng/mL | | Functional Sensitivity | LoQ: 7 ng/mL | Not specified | | Interferences | **Lipemia (Intralipid):** No interference up to 1000 mg/dL on Roche/Hitachi 912/917/Mod P, and 800 mg/dL on Roche/Hitachi 902 **Rheumatoid factors:** No interference up to 1200 IU/mL **Hook effect:** No hook effect up to 80,000 ng/mL | **Lipemia (Intralipid):** No interference up to L-index of 750 (approximate triglyceride concentration: 1500 mg/dL). **Rheumatoid factors:** No interference up to 100 IU/mL **Hook effect:** No hook effect up to 20,000 ng/mL | | Expected Values | Men (20-60 years): 30-400 ng/mL Women (17-60 years): 15-150 ng/mL | Men: 30-400 ng/mL Women: 15-150 ng/mL | K. Standard/Guidance Document Referenced (if applicable): CLSI EP17-A, Protocol for Determination of Limits of Detection and Limits of Quantitative; Approved Guideline CLSI EP5-A2, Evaluation of Precision Performance of Clinical Chemistry Devices; Approved Guideline -2nd ed. L. Test Principle: Tina-Quant Ferritin Assay is an immunoturbidimetric test for the quantitative determination of ferritin in human serum and plasma. During the reaction, anti-ferritin antibodies coupled with latex microparticles react with ferritin in the sample to form an antigen-antibody complex. Following agglutination, the precipitate is measured turbidimetrically. Ferritin concentration is proportional to the amount of turbidity formed. M. Performance Characteristics (if/when applicable): {3} 4 1. Analytical performance: a. Precision/Reproducibility: i. Hitachi 917: Precision study was performed on Hitachi 917 using two controls and five pooled serum samples. Two controls were prepared with Precinorm Protein (PNP) and Precipath Protein (PPP) at 128 ng/mL and 332 ng/mL, respectively. The pooled serum samples were prepared at the following levels: 8.48 ng/mL, 25.5 ng/mL, 235 ng/mL, 618.6 ng/mL, and 820 ng/mL. Samples were tested in duplicate, twice a day for 21 days on Rochi/Hitachi 917, yielding 84 observations for each sample. Results were acceptable within Roche’s assay specification. | Samples | Mean (ng/mL) | Repeatability (Within-Run) | | Intermediate Precision (Between Day) | | | --- | --- | --- | --- | --- | --- | | | | SD (ng/mL) | % CV | SD (ng/mL) | % CV | | PNP | 128 | 1 | 0.9 | 2 | 1.5 | | PPP | 332 | 4 | 1.2 | 7 | 2.0 | | Human serum 1 | 8.48 | 0.6 | 7.2 | 0.8 | 9.9 | | Human serum 2 | 25.5 | 1.2 | 4.7 | 1.3 | 5.2 | | Human serum 3 | 235 | 2 | 0.9 | 4 | 1.8 | | Human serum 4 | 619 | 7 | 1.2 | 13 | 2.1 | | Human serum 5 | 820 | 9 | 1.1 | 17 | 2.1 | ii. Hitachi 902: Repeatability (Within-run) was tested on Hitachi 902 with two controls and four pooled serum samples at the following levels: 11.8 ng/mL, 27.1 ng/mL, 140 ng/mL, 202 ng/mL, 297 ng/mL, and 794 ng/mL. Results were acceptable within Roche’s assay specification. | Samples | Mean (ng/mL) | Repeatability (within-run) | | | --- | --- | --- | --- | | | | SD (ng/mL) | % CV | | PNP | 140 | 1 | 1.1 | | PPP | 297 | 2 | 0.7 | | Human serum 1 | 11.8 | 0.9 | 7.5 | | Human serum 2 | 27.1 | 0.9 | 3.4 | | Human serum 3 | 202 | 2 | 0.8 | | Human serum 4 | 794 | 4 | 0.5 | b. Linearity/assay reportable range: i. Hitachi 917: To determine the linearity, the dilution series were prepared using the high concentration levels of human serum patient samples. The diluted samples covered the concentration range of 0-1229 ng/mL. Each dilution was tested in triplicate. The results were pooled for the regression analyses. The reagent was determined to be linear for the claimed measuring range for Hitachi 917, i.e., 5 - 1000 ng/mL. The provided regression equations are as follows: Passing-Bablok: $$y = 1.0098x - 0.0646$$ (Kandall’s τ = 0.9996) (95% CI of slope 0.9983 to 1.0207 and for intercept -1.1800 to 0.2298) {4} Linear regression: y=1.0249x-2.9729 (Pearson’s r = 0.9998) (95% CI for slope 0.0192 to 1.0305 and for intercept -4.5778 to -1.3680) ii. Hitachi 902: A similar protocol was used to prepare the sample for testing the linearity on Hitachi 902. The concentrations of diluted samples were ranging from 0 - 1385 ng/mL. The provided regression equations are as follows: Passing-Bablok: y=1.1583x+0.7631 (Kandall’s τ =0.9978) (95% CI of slope 1.1456 to 1.1988 and for intercept -0.0840 to 1.6651) Linear regression: y=1.0838x+11.6614 (Pearson’s r = 0.9955) (95% CI for slope 1.0446 to 1.1229 and for intercept 2.5623 to 20.7605) The final claimed reportable range for Hitachi 902 is 5 - 800 ng/mL. c. Traceability, Stability, Expected values (controls, calibrators, or methods): The Tina-Quant Ferritin Gen. 4 assay has been standardized against the Roche Elecsys Ferritin Assay which is traceable to WHO reference materials IS 94/572, 80/578, 80/602. The recommended controls and calibrator for use have been previously cleared. The calibrator, C.f.a.s. Proteins, was cleared in k080607. The controls, Precinorm Protein and Precipath Protein were cleared in k012371. The real time and on-board stability studies were done on Roche/Hitachi 917. Three lots and two controls were tested in triplicate. For real time stability, data were collected at point 0, 6 months, 13 months, 19 months, and 25 months at 2-8°C. The reagent was stable up to 25 months. For on-board stability, data were collected after being stressed for 5 days at 35°C and then at 6 weeks, 8 weeks, 12 weeks at 5-15°C. The reagents were stable up to 12 weeks opened and refrigerated on the analyzer. d. Detection limit: The limit of blank (LoB) and limit of detection (LoD) of the Tina-Quant Ferritin Gen. 4 were determined on Roche/Hitachi 917 in accordance with the CLSI EP17-A requirements. For LoB, one analyte free sample was analyzed in five-fold determinations on two Roche/Hitachi analyzer systems over three days, two runs per day, for a total of N=60 determinations. Two lots of reagent were used for testing. For LoD, five human serum samples with low analyte concentration were analyzed in one-fold determination on two Roche/Hitachi analyzers over three days, two runs per day. Two lots of reagents were used for testing. For LoQ, five human serum samples with concentration ranging from 3.20 ng/mL to 9.65 ng/mL were tested once per day, for 10 days. The LoQ was determined as the lowest analyte concentration that can be reproducibly measured with a between-run %CV ≤ 20%. The LoB is 3 ng/mL, LoD is 5 ng/mL, and LoQ is 7 ng/mL. 5 {5} # e. Analytical specificity: i. Endogenous interference: Effect on quantitation of analyte in the presence of endogenous interfering substances using the Tina-Quant Ferritin Gen. 4 assay was determined by using two levels (33.2-37.4 μg/L and 163-192 μg/L) of pooled human serum samples spiked with varying levels of interferent, including bilirubin (conjugated and unconjugated), hemoglobin, lipemia, and rheumatoid factors. The resulting samples series (ten levels of interferent per sample) were tested in triplicate and the mean values were used to calculate recovery. The provided acceptance criteria for this assay were: within ±4 ng/mL for sample ≤40 ng/mL or within ±10% from sample >40 ng/mL. No significant interference was noted for samples containing less than: Bilirubin (conjugated and unconjugated bilirubin) (60 mg/dL); hemoglobin (500 mg/dL); Lipemia (Intralipid) (1000 mg/dL on Roche/Hitachi 917, 800 mg/dL on Roche/Hitachi 902); and rheumatoid factors (1200 IU/mL). ii. Drug interferences: Eighteen commonly used drugs were added to native patient samples (see table below) and examined for potential interference on ferritin determination by the Tina-Quant Ferritin Gen. 4 test system. Significant interference was defined as ±10% deviation from the reference value. No significant interference was found at therapeutic concentrations of tested drugs. | Name of Agent | Highest Conc. tested (mg/L) | Name of Agent | Highest Conc. tested (mg/L) | | --- | --- | --- | --- | | Acetylcystein | 150 | Methyldopa+1.5 | 20 | | Ampicillin-Na | 1000 | Metronidazole | 200 | | Ascorbic acid | 300 | Phenylbutazone | 400 | | Ca-Dobesilate | 200 | Doxycyclin | 50 | | Cyclosporine A | 5 | Acetylsalycilic acid | 1000 | | Cefoxitin | 2500 | Rifampicin | 60 | | Heparin – Na | 5000 U | Acetaminophen | 200 | | Intralipid | 1000 mg/dL | Ibuprofen | 500 | | Levodopa | 20 | Theophylline | 100 | iii. Hook effect: The possibility of a high-dose hook effect was examined for the Tina-Quant Ferritin Gen. 4 assay using two human serum samples spiked to a theoretical concentration of 100,000 ng/mL. The dilution series were prepared using saline and analyzed. The Hook limit concentration is the maximal concentration giving a signal above the Hook decision limit. No hook effect was detected up to 80,000 ng/mL. f. Assay cut-off: Not applicable 2. Comparison studies: a. Method comparison with predicate device: A method comparison study was performed to compare the Tina-Quant Ferritin Gen. 4 on Roche/Hitachi (y) and the predicate device on the same analyzer (x) using human serum samples. The samples were included to fully {6} span the measuring range. Results were summarized as follows: | Analyzer | N= | Sample range (ng/mL) | Comparison (Passing/Bablok) | | --- | --- | --- | --- | | Hitachi 917 | 94 | 15.0 – 775.3 | y =0.987x+0.040 (τ = 0.983) Slope (95% CI): 0.980 to 0.999 Intercept (95% CI): -1.453 to 2.169 | | Hitachi 902 | 84 | 5.9 – 383.1 | y =0.979x - 1.188 (τ = 0.948) Slope (95% CI): 0.964 to 0.997 Intercept (95% CI): -2.044 to -0.317 | # b. Matrix comparison: To validate different sample matrices, parallel samples were collected in serum, Li-heparin, K2-EDTA, and K3-EDTA plasma tubes. The samples covering the majority of the dynamic range were evaluated on Roche/Hitachi 917. Comparability between matrices was evaluated and the following correlations were obtained. | Matrix compared to serum | N= | Comparison (Passing/Bablok) | | --- | --- | --- | | Li-Heparin | 95 | y =1.020 x -1.259 (τ = 0.981) Slope (95% CI): 1.013 to 1.029 Intercept (95%CI): -2.346 to -0.430 | | K2-EDTA | 94 | y=0.999x -0.877 (τ = 0.987) Slope (95% CI): 0.996 to 1.002 Intercept (95%CI): -1.208 to -0.395 | | K3-EDTA | 95 | y=0.985x -1.800 (τ =0.989) Slope (95% CI): 0.969 to 0.993 Intercept (95% CI): -2.369 to -0.649 | # 3. Clinical studies: a. Clinical Sensitivity: Not applicable b. Clinical specificity: Not applicable c. Other clinical supportive data (when a. and b. are not applicable): Not applicable # 4. Clinical cut-off: Not applicable # 5. Expected values/Reference range: Men (20-60 years): 30-400 ng/mL Women (17-60 years): 15-150 ng/mL # N. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. # O. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision.