DIMENSION AMMONIA FLEX REAGENT CARTRIDGE

K123320 · Siemens Healthcare Diagnostics · JIF · Feb 15, 2013 · Clinical Chemistry

Device Facts

• Record ID: K123320
• Device Name: DIMENSION AMMONIA FLEX REAGENT CARTRIDGE
• Applicant: Siemens Healthcare Diagnostics
• Product Code: JIF · Clinical Chemistry
• Decision Date: Feb 15, 2013
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1065
• Device Class: Class 1

Intended Use

The AMM method is an in vitro diagnostic test for the quantitative measurement of ammonia in human plasma (heparin or EDTA) on the Dimension® clinical chemistry system. Ammonia measurements are used in the diagnosis and treatment of severe liver disorders such as cirrhosis, hepatitis and Reye's syndrome.

Device Story

The Dimension® Ammonia Flex® reagent cartridge (AMM) is an in vitro diagnostic assay for use on the Dimension® clinical chemistry system. It utilizes an enzymatic method involving glutamate dehydrogenase (GLDH) and a stabilized NADPH analog. The device accepts human plasma (heparin or EDTA) as input. Ammonia in the sample reacts with α-ketoglutarate and the reduced cofactor, catalyzed by GLDH, to form L-glutamate and the cofactor. The system monitors the decrease in absorbance at 340/700 nm, which is proportional to the ammonia concentration. The output is a quantitative ammonia measurement provided to clinicians to assist in the diagnosis and management of severe liver disorders. The device is intended for professional use in clinical laboratory settings.

Clinical Evidence

Bench testing only. Method comparison study (n=127) between AMM and predicate showed slope 0.98, intercept 9 µg/dL, and r=1.00. Plasma comparison (n=50) between lithium heparin and EDTA showed slope 0.96, intercept 1.6 µg/dL, and r=1.00. Precision testing (20 days) showed within-lab CVs ranging from 1.3% to 9.3% across three control levels. Linearity established from 17–1277 µg/dL. Interference testing performed per CLSI EP7-A2; no significant interference observed for tested substances within specified limits.

Technological Characteristics

Enzymatic assay using glutamate dehydrogenase (GLDH) and stabilized NADPH analog. Liquid reagent format. Measurement via bichromatic rate at 340/700 nm. Analytical measurement range: 17–1277 µg/dL [10–750 µmol/L]. Designed for use on Dimension® clinical chemistry systems. Complies with CLSI guidelines EP5-A2, EP6-A, EP7-A2, EP9-A2, EP17-A, and C28-A3.

Indications for Use

Indicated for quantitative measurement of ammonia in human plasma (heparin or EDTA) to aid in diagnosis and treatment of severe liver disorders including cirrhosis, hepatitis, and Reye's syndrome.

Regulatory Classification

Identification

An ammonia test system is a device intended to measure ammonia levels in blood, serum, and plasma, Ammonia measurements are used in the diagnosis and treatment of severe liver disorders, such as cirrhosis, hepatitis, and Reye's syndrome.

Predicate Devices

• Dimension® Ammonia (AMON) (k863840)

Submission Summary (Full Text)

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K123320

## 510k Summarv

# FEB 1 5 2013

## Dimension® Ammonia Flex® reagent cartridge (AMM)

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

## 1. 510(k) Number

- 2. Applicant: Rose T. Marinelli Siemens Healthcare Diagnostics, Inc. P.O. Box 6101, Newark, DE 19714-6101 Office Number: 302-631-8805; Fax Number: 302-631-6299
#### 3. Date: October 25, 2012

## 4. Proprietary and Established Names:

Dimension® Ammonia Flex® reagent cartridge, (AMM)

#### 5. Regulatory Information:

Ammonia (AMM) Flex® reagent cartridge

Requlation section: 21 CFR 862,1065 Enzvmatic Method, Ammonia Classification: Class I Product Code: JIF Panel: Clinical Chemistry

#### 6. Predicate Devices:

The predicate device used to demonstrate substantial equivalence to the Dimension® Ammonia (AMM) Flex® reagent cartridge is the Dimension® Ammonia (AMON) previously cleared under k863840.

#### 7. Device Description:

The Dimension® Ammonia assay (AMM) is an enzymatic method that uses glutamate dehydrogenase (GLDH) and a stabilized NADPH analog. Ammonia reacts with a-ketoglutarate and reduced cofactor to form L-glutamate and the cofactor. The reaction is catalyzed by glutamate dehydrogenase. The decrease in absorbance due to the oxidation of the reduced cofactor is monitored at 340/700 nm and is proportional to the ammonia concentration.

GLDH

α-ketoglutarate + NH4* + reduced cofactor ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------L-glutamate + cofactor + H2O

#### 8. Intended Use:

The AMM method is an in vitro diagnostic test for the quantitative measurement of ammonia in human plasma (heparin or EDTA) on the Dimension® clinical chemistry system. Ammonia

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measurements are used in the diagnosis and treatment of severe liver disorders such as cirrhosis, hepatitis and Reve's syndrome.

#### 9. Indication(s) for Use:

The AMM method is an in vitro diagnostic test for the quantitative measurement of ammonia in human plasma (heparin or EDTA) on the Dimension® clinical chemistry system. Ammonia measurements are used in the diagnosis and treatment of severe liver disorders such as cirrhosis, hepatitis and Reye's syndrome.

#### 10. Substantial Equivalence Information:

Both the Dimension® Ammonia Flex® reagent cartridge (AMM) assay and the predicate Dimension® Ammonia Flex® reagent cartridge (AMON) assay employ prepackaged reagents for use on automated clinical chemistry test systems. A comparison of the similarities and differences between the devices is provided in the following tables:

| Feature | New Device : Dimension®<br>Ammonia Flex® reagent<br>cartridge (AMM) | Predicate: Dimension®<br>Ammonia Flex® reagent<br>cartridge (AMON) k863840 |
|--------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | The AMM method is an in vitro<br>diagnostic test for the quantitative<br>measurement of ammonia in<br>human plasma on the Dimension®<br>clinical chemistry system.<br>Ammonia measurements are used<br>in the diagnosis and treatment of<br>severe liver disorders such as<br>cirrhosis, hepatitis and Reye's<br>syndrome. | The AMON method used on the<br>Dimension® clinical chemistry<br>system is an in vitro diagnostic<br>test intended for the quantitative<br>determination of ammonia in<br>human plasma. |
| Format | Prepackaged for use on an<br>automated system | Prepackaged for use on an<br>automated system |
| Measurement | Bichromatic Rate | Bichromatic Rate |

Similarities for Dimension® AMM assay:

## Differences for Dimension® AMM assay:

| Feature | New Device: Dimension®<br>Ammonia Flex® reagent<br>cartridge (AMM) | Predicate: Dimension®<br>Ammonia Flex® reagent<br>cartridge (AMON) k863840 |
|--------------------|--------------------------------------------------------------------|----------------------------------------------------------------------------|
| Measuring<br>Range | 17-1277 µg/dL [10 – 750 µmol/L] | 0 - 1000 µmol/L |
| Sample Size | 44 µL | 53 µL |
| Sample Type | Plasma (Lithium Heparin and<br>EDTA) | Plasma (EDTA, Lithium Heparin,<br>Sodium Fluoride) |
| Reagent<br>Form | Liquid | Tablet |

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Note: Siemens has decided to offer our customers both conventional units and Systéme International d'Unites (Sl units) in the Instructions for Use (IFU). The predicate, Dimension® Ammonia (AMON) assay results are reported in SI Units only. All data supplied in Appendix C will include both conventional units and SI Units for ease of review. Raw data was collected from the instruments in SI units and the conventional units were calculated using the following equation: ug/dL x 0.587 = [umol/L].

## 11. Standard/Guidance Document Reference:

- · Evaluation of Precision Performance of Quantitative Measurement in Methods; Approved Guideline (EP5-A2)
- · Evaluation of the Linearity of Quantitative Measurement Procedures; A Statistical Approach; Approved Guideline (EP6-A)
- · Interference Testing in Clinical Chemistry; Approved Guideline (EP7-A2)
- · Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline (EP9-A2)
- Protocols for Determination of Limits of Detection and Quantitation; Approved Guideline (EP17-A)
- · Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline (C28-A3)

## 12. Performance Characteristics

The following data represent typical performance for the Dimension® clinical chemistry system and were collected on a Dimension® RxL Max.

## Method Comparison

Split sample comparison between the Dimension® Ammonia (AMM) assay and the Dimension® Ammonia (AMON) assay gave the following correlation statistics, when tested with patient samples:

| Dimension® | Predicate | Slope | Intercept<br>µg/dL[µmol/L] | Correlation<br>Coefficient (r) | n |
|------------|--------------------|-------|----------------------------|--------------------------------|-----|
| AMM | Dimension®<br>AMON | 0.98 | 9 [5] | 1.00 | 127 |

# Dimension® Ammonia (AMM) vs. Predicate

#### Plasma Comparison

To demonstrate equivalency between lithium heparin plasma for Dimension® AMM, comparison testing of 50 matched lithium heparin and EDTA plasma samples were tested on the Dimension® System and gave the following linear regression statistics:

| Serum vs. Plasma Comparison Data | | | | |
|----------------------------------|-------|----------------------------|--------------------------------|----|
| Lithium<br>Heparin vs. | Slope | Intercept<br>µg/dL[µmol/L] | Correlation<br>Coefficient (r) | n |
| EDTA | 0.96 | 1.6 [1.0] | 1.00 | 50 |

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#### Reference Interval (Expected Values)

The predicate Dimension® Ammonia (AMON) therapeutic range of 19 – 54 µg/dL [11 – 32 umol/L1 was validated for use with the Dimension® Ammonia (AMM) method by transference following CLSI C28-A3 Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory - Approved Guideline - Third Edition. The Dimension® AMM assay is based on the same intended use and measuring principle as the predicate, Dimension® AMON. The literature reference used was the Textbook of Clinical Chemistry by NW Tietz; WB Saunders Co., Philadelphia, PA; pages 1487-1488.

Samples were collected from 30 healthy adults (17 men and 13 women) and analyzed with the Dimension® AMM method versus the predicate, Dimension® AMON method.

Expected Values: 11 - 32 umol/L [19 - 54 ug/dL] '

#### Precision

Precision testing was performed in accordance with CLSI EPS-A2 Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Second Edition. Samples consisted of three levels of Liquichek™ Ethanol/Ammonia control. Testing was performed over 20 days, two separate runs with two test samples for each test material. Analysis of variance (ANOVA) was used to evaluate the data consistent with the recommendations of EP5-A2. The data are summarized in the following Dimension® Ammonia (AMM) Summary Table:

| Material | Mean<br>µg/dL [µmol/L] | | Standard Deviation (%CV)<br>Repeatability Within-Lab | |
|------------------------------------|------------------------|-------|------------------------------------------------------|-----------------|
| Liquichek™ Ethanol/Ammonia control | | | | |
| Level 1 | 40 | [23] | 2.1 [1.2] (5.2) | 3.7 [2.2] (9.3) |
| Level 2 | 187 | [110] | 2.6 [1.5] (1.4) | 3.7 [2.2] (2.0) |
| Level 3 | 565 | [332] | 3.3 [1.9] (0.6) | 7.3 [4.4] (1.3) |

#### Linearitv

The linear range was determined according to CLSI EP-6A. Evaluation of the Linearity of Quantitative Measurement Procedures; A Statistical Approach; Approved Guideline. Based on the results of this testing and the Limit of Detection testing, the analytical measurement range was determined to be 17 – 1277 µg/dL [10 - 750 µmol/L].

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Image /page/4/Figure/0 description: The image shows a graph with a straight line and several data points plotted along it. The line appears to be a linear regression or a line of best fit for the data points. The data points are closely aligned with the line, indicating a strong positive correlation between the variables represented on the x and y axes. There is also a rectangular box in the lower right quadrant of the graph.

## Analytical Specificity/Interferences

The AMM method was evaluated for interference according to CLSI EP7-A2 Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition. Bias is the difference in the results between the control sample (without the interferent) and the test sample (contains the interferent) expressed in percent. Bias exceeding 10% is considered interference.

| Substance Tested | Substance Concentration | Ammonia<br>µg/dL [µmol/L] | Bias % |
|-----------------------------|-----------------------------------------------------|----------------------------------------------|----------------------|
| Hemoglobin<br>(hemolysate) | 75 mg/dL [0.05 mmol/L]<br>500 mg/dL [0.3105 mmol/L] | 85 [50]<br>426 [250] | +11<br><10 |
| Bilirubin<br>(unconjugated) | 60 mg/dL [1026 µmol/L]<br>80 mg/dL [1368 µmol/L] | 85 [50]<br>426 [50] | <10<br><10 |
| Bilirubin<br>(conjugated) | 80 mg/dL [1368 µmol/L] | 85 [50]<br>426 [250] | <10<br><10 |
| Lipemia<br>(Intralipid®) | 400 mg/dL [4.52 mmol/L]<br>200 mg/dL [2.26 mmol/L] | 85 [50]<br>426 [250]<br>85 [50]<br>426 [250] | *<br>*<br><10<br><10 |

*Lipemia (Intralipid®) at 400 mg/dL [4.52 mmol/L] and above tripped a test report message; interference could not be determined.

Studies were also performed following CLSI EP7-A2 for Interference Testing of exogenous substances at an ammonia concentration of 85 and 426 µg/dL and were found not to interfere with the AMM method when present in plasma. Inaccuracies (biases) were all less than 10%. See Dimension® AMM Instructions for Use for a full list of substances tested.

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#### Interfering Substances

The AMM assay was evaluated for interference according to CLSI/NCCLS EP7-A2. Bias is the difference in the results between the control sample (without the interferent) and the test sample (contains the interferent) expressed in percent. Bias exceeding 10% is considered interference. Testing was performed at two levels of analyte concentration.

| Analyte Test Level | 85 µg/dL<br>[50 mmol/L] | | |
|-----------------------------|-------------------------|--------------------------|-------------|
| Interferent | [Test]<br>mg/dL | [Test] SI<br>Units | Bias<br>(%) |
| Albumin | 6 g/dL | 60 g/L | 61 |
| Bilirubin<br>(unconjugated) | 80mg/dL | 136.8 µmol/L | -25 |
| Dextran 40 | 500 mg/dL | 125 µmol/L | 20 |
| Cholesterol | 503 mg/dL | 13 mmol/L | 73 |
| Creatinine | 30 mg/dL | 2.65 mmol/L | 40 |
| Hemoglobin | 75 mg/dL | 0.05 mmol/L<br>(monomer) | 11 |
| Immunoglobulin G | 5 g/dL | 50 g/L | 32 |
| Uric Acid | 20 mg/dL | 1.2 mmol/L | 56 |

| Analyte Test Level | 426 µg/dL<br>[250 mol/L] | | |
|--------------------|--------------------------|----------------------|-------------|
| Interferent | [Test]<br>mg/dL | [Test] S.I.<br>Units | Bias<br>(%) |
| Albumin | 6 g/dL | 60 g/L | 15 |
| Dextran 40 | 3000 mg/dL | 750 µmol/L | 16 |
| Cholesterol | 503 mg/dL | 13 mmol/L | 34 |
| Uric Acid | 20 mg/dL | 1.2 mmol/L | 16 |

For certain endogenous interferents which exceeded 10 % bias, an aliquot of patient sample containing the potential interferent (test) was mixed with equal parts of a plasma pool containing approximately 85 µg/dL [50 µmo//L] ammonia (control). Test samples and control samples were processed and percent recovery calculated from expected and observed values. No significant interference was observed based on recovery within 10% of expected value.

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| Substance<br>Tested | Test Concentration | | AMM concentration | |
|---------------------|--------------------|-------------|-------------------|----------|
| | conventional | SI unit | µg/dL | [µmol/L] |
| Albumin | 5.4 g/dL | 54 g/L | 170 | [100] |
| Cholesterol | 489 mg/dL | 13 mmol/L | 341 | [200] |
| Creatinine | 21.1 mg/dL | 1.87 mmol/L | 230 | [135] |
| Triglyceride | 1102 mg/dL | 12.5 mmol/L | 363 | [213] |
| Uric Acid | 9.3 mg/dL | 0.6 mmol/L | 145 | [85] |

## Limit of Blank, Limit of Determination and Limit of Quantitation

The Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ) was evaluated in accordance with CLSI EP17-A Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline. Studies were performed on the Dimension® clinical chemistry analyzer with the following results:

| Dimension® Ammonia (AMM) | | |
|--------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|
| Limit | Protocol | Value |
| LoB | 4 samples of calibrator (zero<br>level) were tested for 3 days,<br>one run per day, 2 replicates<br>per run, 2 reagent lots, 1<br>instrument | 5 µg/dL [3 µmol/L] |
| LoD | 4 low level samples were<br>tested for 3 days, one run per<br>day, 2 replicates per run, 2<br>reagent lots, 1 instrument | 11 µg/dL [7 µmol/L] |
| LoQ | 3 ammonia standards each<br>diluted to 17 µg/dL [10 µmol/L]<br>with purified water were tested<br>for 3 days, one run per day, 3<br>replicates per run, 2 reagent<br>lots, 1 instrument | 17 µg/dL [10 µmol/L] |

13. Conclusion: Based on the data presented, the Dimension® Ammonia (AMM) Flex® reagent cartridge is substantially equivalent in principle and performance to the Dimension® Ammonia (AMON) assay,

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/7/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo is circular, with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. In the center of the circle is a stylized symbol that resembles an abstract human figure or a flame-like design.

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

Public Health Service

## February 15, 2013

Siemens Healthcare Diagnostics. Inc. c/o Rose T. Marinelli P.O. Box 6101/MS 514 Newark, DE 19714-6101

Re: k123320

Trade/Device Name: Dimension Ammonia Flex reagent cartridge (AMM) Regulation Number: 21 CFR 862.1065 Regulation Name: Ammonia test system Regulatory Class: I, reserved Product Code: JIF Dated: February 05, 2013 Received: February 07, 2013

Dear Ms. Marinelli:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA), You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please go to http://www.fdaggov/AboutFDA/CentersOffices/CDRH/CDRHOffices/ucm11.5809.htm for

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Page 2-Ms. Marinelli

the Center for Devices and Radiological Health's (CDRH's) Office of Compliance. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number [phone] or [phone] or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Carol C. Benson for

Courtney H. Lias, Ph.D.

. Director

Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics

and Radiological Health

Center for Devices and Radiological Health

Enclosure

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# Indications for Use

510(k) Number (if known): k123320

Device Name: Dimension® Ammonia Flex® reagent cartridge (AMM)

Indications for Use:

The AMM method is an in vitro diagnostic test for the quantitative measurement of ammonia in human plasma (heparin or EDTA) on the Dimension® clinical chemistry system. Ammonia measurements are used in the diagnosis and treatment of severe liver disorders such as cirrhosis, hepatitis and Reye's syndrome

Prescription Use X (21 CFR Part 801 Subpart D)

And/Or

Over the Counter Use (21 CFR Part 801 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostics and Radiological Health (OIR)

Denise Johnson-lyles -S 2013.02.15 10:04:32 -05'00'

Division Sign-Off Office of In Vitro Diagnostics and Radiological Health

k123320 510(k)