OLYMPUS CRP LATEX REAGENT, OSR6199; OLYMPUS CRP LATEX CALIBRATOR NORMAL SET, ODC0026; OLYMPUS CRP LATEX CALIBRATOR HIGH

K051564 · Olympus America, Inc. · NQD · Aug 22, 2005 · Immunology

Device Facts

• Record ID: K051564
• Device Name: OLYMPUS CRP LATEX REAGENT, OSR6199; OLYMPUS CRP LATEX CALIBRATOR NORMAL SET, ODC0026; OLYMPUS CRP LATEX CALIBRATOR HIGH
• Applicant: Olympus America, Inc.
• Product Code: NQD · Immunology
• Decision Date: Aug 22, 2005
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.5270
• Device Class: Class 2

Indications for Use

Olympus System Reagent and calibrators for the quantitative determination of C-Reactive Protein in human serum and plasma on OLYMPUS Analyzers. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be used as an aid in the identification of individuals at risk of future cardiovascular disease. High sensitivity CRP (hsCRP) measurements, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, maybe useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes.

Device Story

Olympus CRP Latex Immunoturbidimetric Reagent and Calibrators are in vitro diagnostic reagents used on Olympus Analyzers. The device utilizes latex-enhanced immunoturbidimetric technology to measure C-Reactive Protein (CRP) levels in human serum or plasma samples. The principle of operation involves an antigen-antibody reaction between CRP in the patient sample and anti-CRP antibodies coated on latex particles, resulting in turbidity proportional to the CRP concentration. The analyzer measures this turbidity to provide a quantitative result. Used in clinical laboratory settings by trained laboratory personnel. Results assist clinicians in diagnosing inflammatory conditions, evaluating tissue injury/infection, and assessing cardiovascular risk. The device provides objective data to support clinical decision-making regarding patient prognosis and management of coronary syndromes.

Clinical Evidence

No clinical data provided in the document; substantial equivalence is based on bench testing and performance characteristics typical of immunoturbidimetric reagent systems.

Technological Characteristics

Reagent: latex particles coated with rabbit anti-CRP antibodies. Calibrators: liquid human serum-based, 5-level set. Measurement: immunoturbidimetric (light scatter/absorbance). Energy: optical (turbidimetry). Connectivity: integrated with Olympus AU-series clinical chemistry analyzers. Sterilization: N/A (reagent). Software: embedded analyzer firmware for data processing and concentration calculation.

Indications for Use

Indicated for quantitative determination of C-Reactive Protein in human serum and plasma for detection/evaluation of infection, tissue injury, inflammatory disorders, and cardiovascular disease risk assessment. Used as prognostic marker for recurrent events in patients with stable coronary disease or acute coronary syndromes.

Regulatory Classification

Identification

A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.

Submission Summary (Full Text)

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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY
ASSAY ONLY TEMPLATE

A. 510(k) Number:
k051564

B. Purpose for Submission:
New Device

C. Measurand:
C-reactive protein

D. Type of Test:
Quantitative

E. Applicant:
Olympus

F. Proprietary and Established Names:
OLYMPUS CRP Latex reagent
OLYMPUS CRP Latex Calibrator Normal Set
OLYMPUS CRP Latex Calibrator Highly Sensitive Set

G. Regulatory Information:
1. Regulation section:
21 CFR 866.5270 C-reactive protein immunological test system
21 CFR 862.1150 Calibrator
2. Classification:
Class II

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3. Product code:
NQD, cardiac c-reactive protein, antigen, antiserum, and control
JIT, calibrator, secondary

4. Panel:
82 Immunology
75 Chemistry

H. Intended Use:

1. Intended use(s):
See indications for use statement below.

2. Indication(s) for use:
Olympus System Reagent and calibrators for the quantitative determination of C-Reactive Protein in human serum and plasma on OLYMPUS Analyzers. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be used as an aid in the identification of individuals at risk of future cardiovascular disease. High sensitivity CRP (hsCRP) measurements, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, maybe useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes.

3. Special conditions for use statement(s):
For prescription use only

4. Special instrument requirements:
OLYMPUS AU400/AU400E, AU600/AU600E, AU2700 and AU5400 Clinical Chemistry Analyzers.

I. Device Description:
The Olympus CRP Latex reagent is an in vitro diagnostic device that consists of ready to use buffer and latex particles coated with rabbit anti-CRP antibodies. Depending on the application used (different instrument settings), two measuring ranges are available: Normal application (CRP Concentrations ranging between 1.0-480 mg/L) and Highly Sensitive (Cardiac/ Neonatal) Application- (CRP concentrations ranging between 0.2- 160 mg/L.

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The CRP Latex Calibrator set (both normal and highly sensitive) is a five level calibrator set. The Olympus CRP Calibrator is a liquid human serum based product assayed for levels of C-reactive protein. Constituent values are adjusted where necessary by the addition of analytical grade serum proteins.

Each human serum donor used in the preparation of the calibrator material was tested by a FDA approved method for the presence of the antibody to HIV-1/2 and HCV as well as for hepatitis B surface antigen and was not repeatedly reactive.

## J. Substantial Equivalence Information:

1. Predicate device name(s):

OLYMPUS CRP Latex Immunoturbidimetric Reagent

2. Predicate 510(k) number(s):

k041668

3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Intended Use | Olympus System Reagent and calibrators for the quantitative determination of C-Reactive Protein on OLYMPUS Analyzers. Measurements of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be used as an aid in the identification of individuals at risk of future cardiovascular disease. High sensitivity CRP (hsCRP) measurements, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, maybe useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes. | Olympus System Reagent and calibrators for the quantitative determination of C-Reactive Protein on OLYMPUS Analyzers. Measurements of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be used as an aid in the identification of individuals at risk of future cardiovascular disease. High sensitivity CRP (hsCRP) measurements, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, maybe useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary |

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| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| | | syndromes. |
| Calibrator Preparation | Liquid stable ready to use Human serum based calibrators | Liquid stable ready to use Human serum based calibrators. |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Application | 2 Applications- Normal (NA) and Highly Sensitive (HS) (Cardiac/Neonatal) | 3 Applications- Normal (NA), Sensitive (Cardiac), Highly Sensitive (HS) |
| Range | Normal- 1.0-480 mg/L and Highly Sensitive- 0.2-160 mg/L | Normal- 5-170 mg/L, Sensitive- 0.5-20.0 mg/L and Highly Sensitive- 0.05-2.00 mg/L. |
| Matrix | Serum and Plasma | Serum |
| Calibrator Application | 2 Application- Normal and Highly Sensitive | 1 Application- CRP normal |
| Calibrator Manufacture | OEM Supplied | In house |
| Zero Calibrator | 0.9% Saline | None |

# K. Standard/Guidance Document Referenced (if applicable):

NCCLS Evaluation Protocols:

EP6-P Evaluation of the linearity of quantitative analytical methods.

EP5-A Evaluation of precision performance of clinical chemistry devices.

EP7-P Interference testing in clinical chemistry.

EP9-A Method comparison and bias estimation using patient samples

# L. Test Principle:

Immune complexes formed in solution scatter light in proportion to their size, shape, and concentration. Turbidimeters measure the reduction of incidence light due to reflection, absorption, or scatter. In this procedure, the measurement of the rate of decrease in light intensity transmitted (increase in absorbency) through particles suspended in solution is the result of complexes formed during the immunological reaction between the CRP of the patient serum and rabbit antibodies coated on latex particles.

# M. Performance Characteristics (if/when applicable):

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1. Analytical performance:

a. Precision/Reproducibility:

Precision was conducted and within run and total CV was calculated according to NCCLS EP5-A. Three sample pools were tested twice daily for twenty days (the highly sensitive application measured medically relevant points for 10 days) with serum based controls. Both applications were tested on all 6 OLYMPUS analyzers and are summarized in the charts below.

OLYMPUS AU400/400*

| N=80 | Within Run | | Total | |
| --- | --- | --- | --- | --- |
| Mean, mg/L | SD | CV% | SD | CV% |
| Normal Application | | | | |
| 6.44 | 0.05 | 0.80 | 0.20 | 3.12 |
| 64.02 | 0.56 | 0.87 | 1.83 | 2.86 |
| 137.70 | 1.02 | 0.74 | 3.63 | 2.63 |
| Highly Sensitive (Cardiac/ Neonatal) Application | | | | |
| 1.01 | 0.02 | 1.53 | 0.02 | 2.32 |
| 3.01 | 0.02 | 0.76 | 0.0 | 1.22 |
| 9.80 | 0.08 | 0.86 | 0.15 | 1.50 |

OLYMPUS AU600/640/640*

| N=80 | Within Run | | Total | |
| --- | --- | --- | --- | --- |
| Mean, mg/L | SD | CV% | SD | CV% |
| Normal Application | | | | |
| 6.56 | 0.07 | 1.009 | 0.12 | 1.85 |
| 64.79 | 0.78 | 1.20 | 2.16 | 3.34 |
| 137.71 | 0.96 | 0.70 | 2.26 | 1.64 |
| Highly Sensitive (Cardiac/ Neonatal) Application | | | | |
| 1.05 | 0.03 | 2.96 | 0.03 | 2.50 |
| 2.99 | 0.02 | 0.62 | 0.03 | 0.92 |
| 10.00 | 0.09 | 0.95 | 0.15 | 1.53 |

OLYMPUS AU2700/5400

| N=80 | Within Run | | Total | |
| --- | --- | --- | --- | --- |
| Mean, mg/L | SD | CV% | SD | CV% |
| Normal Application | | | | |
| 6.59 | 0.21 | 3.22 | 0.25 | 3.79 |
| 62.84 | 0.64 | 1.02 | 1.21 | 1.92 |
| 137.52 | 1.28 | 0.93 | 2.27 | 1.65 |
| Highly Sensitive (Cardiac/ Neonatal) Application | | | | |
| 1.03 | 0.03 | 3.22 | 0.03 | 2.78 |
| 3.05 | 0.04 | 1.21 | 0.04 | 1.33 |
| 9.70 | 0.09 | 0.92 | 0.19 | 1.94 |

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b. Linearity/assay reportable range:

Linearity was conducted and checked according to NCCLS EP6-A. A series of 10 dilutions of a high pool sample are run in quadruplicate on each of the 6 instruments and the mean results were plotted versus the relative analyte concentrations. Linearity was also conducted with the reagent after being onboard the analyzer for 30 days. The best fit line was determined by linear regression and the sponsor's acceptance criteria are as follows:

Normal Application- 1.0- 480 mg/L [less than 10% or 2.0 mg/L SD]

Highly Sensitive Application- 0.2-160 mg/L [less than 12% or 0.15 mg/L SD]

The following results are for the instruments, applications and ranges indicated.

AU400

| Application | Range | N | Slope | Intercept |
| --- | --- | --- | --- | --- |
| Normal | 0.090 – 52.393 | 7 | 0.949 | -0.118 |
| Normal | 0.090 – 471.730 | 11 | 1.044 | 1.012 |
| Normal | 0.013- 539.333 | 11 | 1.014 | -0.641 |
| Normal (30 day onboard) | 0.035- 491.750 | 11 | 1.023 | -0.795 |
| Highly Sensitive (low) | 0.0- 21.683 | 7 | 1.022 | -0.018 |
| Highly Sensitive | 0.017 – 175.420 | 11 | 1.037 | -0.053 |
| Highly Sensitive (30 day onboard) | 0.010 – 171.910 | 11 | 1.025 | -0.045 |

AU640

| Application | Range | N | Slope | Intercept |
| --- | --- | --- | --- | --- |
| Normal | 0.008 – 53.847 | 7 | 0.951 | -0.040 |
| Normal | 0.008 – 481.678 | 11 | 1.016 | 1.339 |
| Normal | 0.055 – 483.043 | 11 | 1.032 | 0.728 |
| Normal (30 day onboard) | 0.040 – 489.560 | 11 | 1.031 | 0.372 |
| Highly Sensitive (low) | -0.035 - 171.738 | 7 | 1.098 | 0.088 |
| Highly Sensitive | 0.015 – 174.058 | 11 | 1.043 | -0.063 |
| Highly Sensitive (30 day onboard) | 0.005 – 170.170 | 11 | 1.045 | -0.070 |

AU 2700

| Application | Range | N | Slope | Intercept |
| --- | --- | --- | --- | --- |
| Normal | -0.010 – 52.113 | 7 | 0.966 | 0.293 |
| Normal | -0.010 – 488.428 | 11 | 1.028 | 0.565 |
| Normal | 0.018 – 498.578 | 11 | 1.003 | 0.359 |
| Normal (30 day onboard) | -0.13 – 481.714 | 11 | 1.029 | -0.9126 |
| Highly Sensitive (low) | -0.050 – 176.315 | 11 | 1.003 | 0.359 |
| Highly Sensitive | 0.000 – 169.178 | 11 | 1.032 | -0.101 |
| Highly Sensitive (30 day onboard) | -0.008 – 170.373 | 11 | 1.038 | 0.047 |

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c. Traceability, Stability, Expected values (controls, calibrators, or methods):

The CRP Latex calibrators (normal and highly sensitive) are liquid human serum matrix containing a predetermined level of human CRP that is traceable to an external standard.

The unopened product is stable for 24 months at 2-8° C. Open product is stable for 30 days when stored in the analyzers' refrigerated compartments-(see linearity data for 30 day onboard stability). Recovery studies were conducted for 3 lots of calibrators and the results are summarized in the chart below. The sponsor recommends using 0.9% saline as a zero calibrator.

| Calibrator CRP concentration | Mean Recovery Range (%) | Application |
| --- | --- | --- |
| 2.5 mg/L | 92-100 | Highly Sensitive |
| 10 | 98-100 | Normal and Highly Sensitive |
| 20 | 98-99 | Highly Sensitive |
| 40 | 95-100 | Normal |
| 80 | 98-100 | Highly Sensitive |
| 160 | 97-101 | Normal and Highly Sensitive |
| 320 | 98-100 | Normal |
| 480 | 98-100 | Normal |

d. Detection limit:

The lower limit of detection was determined by testing an analyte-free sample twenty-fold on each of the 6 instruments. The lower limit of detection was calculated as the mean plus three times the standard deviation. The results met the sponsor's criteria of less than 0.15 mg/L for the normal application and less than 0.07 mg/L for the highly sensitive application and are listed in the table below.

| Instrument | Application | Mean | SD | LLD |
| --- | --- | --- | --- | --- |
| AU400 | Normal | 0.02 | 0.027 | 0.10 mg/L |
| AU640 | Normal | 0.02 | 0.024 | 0.09 mg/L |
| AU2700 | Normal | 0.03 | 0.036 | 0.135 mg/L |
| AU400 | Highly Sensitive | 0.00 | 0.006 | 0.02 mg/L |
| AU640 | Highly Sensitive | 0.00 | 0.007 | 0.02 mg/L |
| AU2700 | Highly Sensitive | 0.22 | 0.14 | 0.065 mg/L |

e. Analytical specificity:

Interference evaluations were conducted and performed based on the NCCLS EP7-P. A pooled sample with analyte level corresponding to a medical

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decision point for the assay was used. The sample was spiked with different levels of the potential interferent up to the maximum level which could be present in samples and tested four-fold at each level. The mean analytical result at each level is compared with that for the non-spiked sample. Interference from Bilirubin, hemolysis and lipemia results are shown below and are reported in the package insert.

Inaccuracies due to bilirubin (40 mg/dL) are less than 5% at CRP concentrations of 1.0 mg/L.

Inaccuracies due to hemolysate (500 mg/dL) are less than 5% at CRP concentrations of 1.0 mg/L.

Inaccuracies due to intralipid* (1000 mg/dL) are less than 10% at CRP concentrations of 1.0 mg/L.

f. Assay cut-off:

Not applicable

2. Comparison studies:

a. Method comparison with predicate device:

Method comparison was performed based on NCCLS EP9-A. The current Olympus C-reactive Protein Reagent was compared to the predicate Olympus C-reactive Protein Reagent using the AU600 as the reference analyzer.

| Normal Application | | | |
| --- | --- | --- | --- |
| Y Method | AU640 | AU2700 | AU400 |
| X Method | Predicate | AU640 | AU640 |
| Slope | 1.024 | 0.998 | 1.023 |
| Intercept | 0.594 | -0.390 | -.393 |
| Correlation Coeff. | 0.998 | 0.999 | 1.000 |
| # of Samples | 113 | 114 | 68 |
| Range (mg/L) | 0.78 to 167.38 | 0.96 to 477.89 | 1.04 to 456.01 |
| Highly Sensitive Application | | | |
| Y Method | AU640 | AU2700 | AU400 |
| X Method | Method 2 | AU640 | AU640 |
| Slope | 0.993 | 1.039 | 1.025 |
| Intercept | -0.825 | -0.569 | -0.022 |
| Correlation Coeff. | 0.997 | 0.999 | 0.999 |
| # of Samples | 118 | 105 | 109 |
| Range (mg/L) | 0.20 to 155.86 | 0.40 to 143.52 | 0.28 to 147.21 |

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A separate method comparison study was also conducted for 60 samples that ranged between 0.59 and 8.87 mg/L using the highly sensitive application. The linear regression statistics were as follows: Slope = 1.018, intercept = 0.177, r = 0.999.

All samples were tested in duplicate for 5 days.

b. Matrix comparison:

A matrix comparison study was performed between serum and plasma (EDTA and Lithium Heparin treated) using the proposed new Olympus C-reactive protein reagent for the both applications on a maximum of 30 patient samples.

EDTA plasma versus serum (normal application) revealed a linear regression equation of Y = 0.984X - 0.001 with a correlation coefficient of 0.999 on 19 samples ranging from 1.01 to 7.22 mg/L.

EDTA plasma versus serum (highly sensitive) gave a linear regression equation of Y = 0.973X + 0.015 with a correlation coefficient of 1.000 on 28 samples ranging from 0.41 to 6.13 mg/L.

Lithium Heparin plasma versus serum (normal application) revealed a linear regression equation of Y = 0.979X - 0.013 with a correlation coefficient of 1.000 on 2 samples ranging from 1.01 to 7.22 mg/L.

Lithium Heparin plasma versus serum (highly sensitive) revealed a linear regression equation of Y = 0.976X + 0.018 with a correlation coefficient of 0.999 on 28 samples ranging from 0.41 to 6.13 mg/L.

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:

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Not applicable

5. Expected values/Reference range:

The expected values of CRP concentrations < 1 mg/L was established through literature, and the cardiac risk assessment categories are recommended by the American Heart Association (AHA) are as follows:

Low < 1 mg/L, Average 1.0 to 3.0 mg/L and High > 3.0 mg/L

Newborns with no evidence of infection have CRP concentrations of < 1 mg/L (established through literature).

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.

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