N ANTISERA TO HUMAN IMMUNOGLOBULINS (IGG, IGA AND IGM)

{0} 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY DEVICE ONLY TEMPLATE A. 510(k) Number: K042735 B. Purpose for Submission: Modified device C. Analyte: IgG, IgA, IgM D. Type of Test: IgG, IgA, IgM: serum, heparinized (sodium heparin, ammonium heparin, and lithium heparin) and EDTA plasma IgG: CSF E. Applicant: Dade Behring Inc. F. Proprietary and Established Names: N Antisera to Immunoglobulins (IgG, IgA, and IgM) Assay G. Regulatory Information: 1. Regulation section: 21 CFR 866.5510 Immunoglobulins A,G,M,D,E immunological test system 2. Classification: Class II 3. Product Code: CFN, Method, Nephelometric, Immunoglobulins (G,A,M) 4. Panel: Immunology H. Intended Use: 1. Intended use(s): In vitro diagnostic reagents for the quantitative determination of immunoglobulins (IgG, IgA and IgM) in human serum, heparinized and EDTA plasma as well as IgG in human cerebrospinal fluid (CSF) by means of immunonephelometry on the BN™ Systems. 2. Indication(s) for use: In vitro diagnostic reagents for the quantitative determination of immunoglobulins (IgG, IgA and IgM) in human serum, heparinized and EDTA plasma as well as IgG in human cerebrospinal fluid (CSF) using the {1} $\mathrm{BN}^{\mathrm{TM}}$ Systems. Measurements of these immunoglobulins aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents. 3. Special condition for use statement(s): For prescription use only 4. Special instrument Requirements: $\mathrm{BN}^{\mathrm{TM}}$ Systems including $\mathrm{BN}^{\mathrm{TM}}$ 100, $\mathrm{BN}^{\mathrm{TM}}$ II System, and $\mathrm{BN}^{\mathrm{TM}}$ ProSpec System. | Feature | BN™ 100 | BN™ II System | BN™ ProSpec | | --- | --- | --- | --- | | 1. Intended Use | The BN™ 100 allows fully automatic determination of proteins in various body liquids. Precipitation as well as agglutination reactions (latex) can be performed quantitatively and quickly | The BN™ II is a system for the quantitative determination of proteins in serum, plasma, urine, and CSF. | The BN™ ProSpec is a system for the quantitative determination of proteins in serum, plasma, urine, and CSF | | 2. Measuring Methods | Nephelometry | Nephelometry | Nephelometry | | 3. Measuring Principles | End-point measurement; Fixed-time kinetic measurement | End-point measurement; Fixed-time kinetic measurement; VLinIntegral | End-point measurement; Fixed-time kinetic measurement; VLinIntegral | | 4. Physical characteristics: | | | | | a. Light Sources | LED | LED | LED | | b. Wavelengths | 840 nm | 840 nm | 840 nm | | c. Pipetting | Yes | Yes | Yes | | d. Interfacing | Bi-directional | Bi-directional | Bi-directional, host query, ASTM | | e. Data Input/Output | Computer & Printer | Computer & Printer | Computer & Printer | | f. Barcode Identification | Yes | Yes | Yes | | g. Dimensions | 47.3 x 94 x5 1 cm (h x w x d) | 71.5 x 124 x 63 cm (h x w x d) | 66 x 110 x 66 cm (h x w x d) | | h. Dilutor Volume | 500 μL | Left 1000 μL (Variable) Middle 2500 μL (Variable) Right 250 μL (Variable) | 500 μL (Variable) | | i. Transfer Arm | 1 | 2 | 1 | | j. Transfer Arm | 1 | 2 | 1 | | k. Transfer Arm | 1 | 2 | 1 | | l. Transfer Arm | 1 | 2 | 1 | {2} # I. Device Description: The device consists of N antiserum to human IgG; N antiserum to human IgA, N antihuman IgM. One vial each containing $5\mathrm{mL}$ or $2\mathrm{mL}$ . # J. Substantial Equivalence Information: 1. Predicate device name(s): N Antisera to Human Immunoglobulins (IgG, IgA, and IgM) Assay 2. Predicate K number(s): K860894 3. Comparison with predicate: | Similarities | | | | | --- | --- | --- | --- | | Item | Device | Predicate | | | Reagents | Modified N Antisera to Human Immunoglobulins | N Antisera to Human Immunoglobulins | | | Instrument | N Antiserum to human IgG,A,M | Same | | | | BN™ Systems | Same | | | Instruments | N Antisera to Human Immunoglobulins | N Antisera to Human Immunoglobulins | | | Instruments | N Antisera to Human IgA | N Antisera to Human IgA | | | Instruments | N Antisera to Human IgA | N Antisera to Human IgA | | {3} Page 4 of 10 | Differences | | | | --- | --- | --- | | Item | Device | Predicate | | Sample Type | IgG,A,M: serum, heparinized and EDTA plasma. IgG: CSF | IgG,A,M: serum IgG: CSF | K. Standard/Guidance Document Referenced (if applicable): Not referenced L. Test Principle: Proteins contained in human body fluids from immune complexes in an immunochemical reaction with specific antibodies. These complexes scatter a beam of light passes through the sample. The intensity of the scattered light is proportional to the concentration to the concentration of the relevant protein in the sample. The result is evaluated by comparison with a standard of known concentration. M. Performance Characteristics (if/when applicable): 1. Analytical performance: a. Precision/Reproducibility: The intra-assay precision The intra-assay precision was determined by using three concentration levels of specimen over five days, testing two independent runs per day (am/pm), assaying four replicates (e.g. 5 x 2 x 4 = 40 replicates). IgG 5.0g/L 3.0% CV 8.4g/L 1.8% CV 12.1 g/L 2.6% CV IgA 1.0 g/L 1.6% CV 1.7g/L 3.3% CV 2.5 g/L 2.5% CV IgM 0.27 g/L 3.8% CV 0.69g/L 3.2% CV 0.90 g/L 2.6% CV {4} Page 5 of 10 ## The inter-assay precision The inter-assay precision was determined by using three levels of concentration specimen. The samples were assayed in two independent run with 4 replicates in 5 days (n=40) IgG 5.0g/L 2.1% CV 8.4g/L 1.4% CV 12.1 g/L 1.5% CV IgA 1.0 g/L 3.7% CV 1.7g/L 2.7% CV 2.5 g/L 2.1% CV IgM 0.27 g/L 4.0% CV 0.69g/L 1.9% CV 0.90 g/L 1.7% CV Total precision IgG 5.0g/L 3.4% CV 8.4g/L 2.7% CV 12.1 g/L 2.1% CV IgA 1.0 g/L 4.1% CV 1.7g/L 4.0% CV 2.5 g/L 3.1% CV IgM 0.27 g/L 5.3% CV 0.69g/L 3.4% CV 0.90 g/L 2.8% CV ## b. Linearity/assay reportable range: The assay ranges for serum or plasma specimens of the N Antisera to human Immunoglobulins G,A,M are approximately: IgG 1.4 to 46 g/L (1:400 dilution) IgA 0.25 to 8.0 g/L (1:20 dilution) IgAs 0.06 to 2.0 g/L (1:5 dilution) IgM 0.2 to 6.4 g/L (1:20 dilution) IgMs 0.05 to 1.6 g/ (1:5 dilution) {5} Page 6 of 10 The assay ranges for CSF specimens of the N Antisera to human Immunoglobulins G is approximately: CSF IgG 3.6 to 115 mg/L. **(Methods and acceptance criteria undisclosed)** c. Traceability (controls, calibrators, or method): The device does not contain controls and calibrators. d. Detection limit: Typical lower limit of the detection are: Serum or plasma IgG 0.19 g/L, CSF IgG 0.5 mg/L Serum or plasma IgA 0.016 g/L Serum or plasma IgM 0.043 g/L The analytical sensitivity of the assay is established by the lower limit of the reference curve, and depend upon the concentrations of the proteins in N Protein Standard SL. e. Analytical specificity: The specificity of the N Antisera Human Immunoglobulins (IgG, IgA, and IgM) assay were tested against normal human serum and plasma pool, antigens to human, and preparations of human IgG, IgA, IgM and Bence-Jonse proteins, type Kappa and Lambda in different analytical methods. There are no known cross-reactivities of the antisera. f. Assay cut-off: IgG 7.0 to 16.0 g/L IgA 0.7 to 4.0 g/L IgM 0.4 to 2.3 g/L 2. Comparison studies: a. Method comparison with predicate device: One hundred (100) serum samples were assayed with N Antisera to humanimmunoglobulins on a BN System ii (y) and a radial immunodiffusion (RID) method (x). Correlation of the results yielded following data: | Protein | Coefficient of correlation | | --- | --- | | IgG y(BN) = 1.09X (RID) - 0.12 g/L | 0.97 | | IgA y(BN) = 0.99X (RID) + 0.06 g/L | 0.99 | | IgM y(BN) = 1.08X (RID) - 0.06 g/L | 0.99 | b. Matrix comparison: Serum/Heparin Plasma Comparison-BN II IgG (n=67) {6} Page 7 of 10 Heparin plasma sample = 0.973 serum sample + 0.068 g/L 95% Confidence Interval Slope (0.953, 0.997) Intercept (-0.068, 0.263) Pearson correlation coefficient (r = 0.989; r² = 0.978) NOTE: Recovery study showed deviation of heparinized plasma for IgG assay (lithium Heparin vs. Sodium Heparin -1.158%; lithium Heparin vs. Ammonium Heparin -0.153%; Ammonium Heparin vs. Sodium Heparin -1.007%) IgA (n=65) Heparin plasma sample = 0.988 serum sample - 0.008 g/L 95% Confidence Interval Slope (0.973, 1.005) Intercept (-0.026, 0.012) Pearson correlation coefficient (r = 0.998; r² = 0.997) NOTE: Recovery study showed deviation of heparinized plasma for IgA assay (lithium Heparin vs. Sodium Heparin -2.94%; lithium Heparin vs. Ammonium Heparin -4.08%; Ammonium Heparin vs. Sodium Heparin -1.19%) IgM (n=64) Heparin plasma sample = 0.981 serum sample + 0.006 g/L 95% Confidence Interval Slope (0.953, 1.011) Intercept (-0.018, 0.024) Pearson correlation coefficient (r = 0.991; r² = 0.982) NOTE: Recovery study showed deviation of heparinized plasma for IgM assay (lithium Heparin vs. Sodium Heparin 0.6%; lithium Heparin vs. Ammonium Heparin -0.151%; Ammonium Heparin vs. Sodium Heparin 0.752%) Serum/EDTA Plasma Comparison-BN II IgG (n=37) EDTA plasma sample = 1.012 serum sample - 0.274 g/L 95% Confidence Interval Slope (0.967, 1.051) Intercept (-0.557, 0.003) Pearson correlation coefficient (r = 0.988; r² = 0.976) IgA (n=36) EDTA plasma sample = 0.961 serum sample - 0.011 g/L 95% Confidence Interval Slope (0.933, 0.998) {7} Page 8 of 10 Intercept (-0.041, 0.024) Pearson correlation coefficient (r = 0.994; r² = 0.989) IgM (n=36) EDTA plasma sample = 0.939 serum sample + 0.004 g/L 95% Confidence Interval Slope (0.892, 0.982) Intercept (-0.014, 0.031) Pearson correlation coefficient (r = 0.980; r² = 0.961) 3. Clinical studies: a. Clinical sensitivity: n/a b. Clinical specificity: n/a c. Other clinical supportive data (when a and b are not applicable): n/a 4. Clinical cut-off: Refer to 1/f 5. Expected values/Reference range: The reference intervals for serum or plasma were derived from a consensus document of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP Reference material (CRM 470). IgG 7.0 to 16.0 g/L IgA 0.7 to 4.0 g/L IgM 0.4 to 2.3 g/L (Reference: Dati F Schumann G., Thomas L., et al. Consensus of a Group of Professional Societies and Diagnostics Companies on guidelines for Interim Reference Ranges for 14 proteins in Serum Based on the Standardization against the IFCC/BCR/CAP Reference Material (CRM 470). International Federation of Clinical Chemistry. Community Bureau of Reference of the Commission of the European Communities. College of American Pathologists. Eur J Clin Chem Clin Biochem 1996; 34:517-520). Reference interval for IgG in CSF sample is less than 34 mg/L. (References: 1. Felgenhauer K. Laboratory Diagnosis of Neurological Disease. In: Thomas L ed. Clinical Laboratory Diagnostics. Frankfurt TH Books Verlagsgesellschaft, 1998:1308-26. 2. Reiber H, Peter JB, Cerebrospinal Fluid Analysis: Disease-related Data Patterns and Evaluation Programs. J Neurol Sci. 2001; 184:101-122). {8} Page 9 of 10 References range (2.5th-97.5th percentile) for childhood and aldolescence: IgG | Age (years) | Male (g/L) | Female (g/L) | | --- | --- | --- | | 1 | 3.5-8.6 | 4.0-9.8 | | 4 | 5.1-12.6 | 5.3-13.0 | | 7 | 6.0-14.7 | 5.9-14.6 | | 10 | 6.6-6.2 | 6.4-15.9 | | 14 | 6.6-16.2 | 6.8-16.7 | | 18 | 6.5-16.0 | 6.9-17.0 | IgA | Age (years) | Male (g/L) | Female (g/L) | | --- | --- | --- | | 1 | 0.17-0.96 | 0.17-0.94 | | 4 | 0.36-1.98 | 0.33-1.85 | | 7 | 0.48-2.66 | 0.44-2.44 | | 10 | 0.57-3.18 | 0.52-2.90 | | 14 | 0.64-3.52 | 0.62-3.43 | | 18 | 0.68-3.79 | 0.69-3.80 | IgM | Age (years) | Male (g/L) | Female (g/L) | | --- | --- | --- | | 1 | 0.30-1.83 | 0.34-2.06 | | 4 | 0.35-2.13 | 0.42-2.55 | | 7 | 0.37-2.26 | 0.45-2.78 | | 10 | 0.38-2.35 | 0.48-2.94 | | 14 | 0.40-2.44 | 0.50-3.09 | | 18 | 0.41-2.51 | 0.52-3.22 | (Reference: Richie RF, Palomaki GE, Neveux LM et al. Reference Distributions for Immunoglobulins A, G, and M: a practical, simple, and clinical relevant approach in a large cohort. J Clin Lab Anal. 1998; 12:263-270). N. Conclusion: The submitted material in this premarket notification is complete and supports a substantial equivalence decision. {9} Page 10 of 10 O. Other Supportive Information: n/a P. Administrative Information: 1. Applicant contact information: a. Name of applicant: Dade Behring Inc. b. Mailing address: Glasgow Business Community P.O. Box 6101, M.S. 514 Newark, DE 19714-6101 c. Phone #: 781-826-4551 d. Fax #: 781-826-2497 e. E-mail address (optional): kathleen-dray-lyons@dadebehring.com f. Contact: 2. Review documentation: Q. Reviewer Name and Signature: