ONLINE TDM Vancomycin Gen.3

K152245 · Roche Diagnostics Operations (Rdo) · LEH · Jan 8, 2016 · Clinical Toxicology

Device Facts

• Record ID: K152245
• Device Name: ONLINE TDM Vancomycin Gen.3
• Applicant: Roche Diagnostics Operations (Rdo)
• Product Code: LEH · Clinical Toxicology
• Decision Date: Jan 8, 2016
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3950
• Device Class: Class 2

Intended Use

In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems. A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.

Device Story

ONLINE TDM Vancomycin Gen.3 is a two-reagent competitive immunoassay for quantitative vancomycin measurement in human serum/plasma; used on Roche/Hitachi cobas c 501 analyzers. Reagents include vancomycin-conjugated macromolecule and anti-vancomycin antibody-coupled latex microparticles. Principle: kinetic interaction (aggregation) of microparticles is inhibited by vancomycin in patient sample; absorbance change is inversely proportional to drug concentration. Operated by laboratory personnel in clinical chemistry settings. Output provides quantitative vancomycin concentration (μg/mL) to clinicians for therapeutic drug monitoring (TDM) and overdose management; helps optimize dosing to balance therapeutic efficacy against risks of nephrotoxicity and ototoxicity.

Clinical Evidence

Bench testing only. Performance validated via precision (CLSI EP5-A2), linearity (CLSI EP6-A), and detection limits (CLSI EP17-A2). Method comparison study (n=125) vs. predicate yielded y = 0.993x + 0.641 (r=0.994). Comparison vs. LC-MS/MS (n=134) yielded y = 0.992x + 0.841 (r=0.991). Interference testing confirmed no significant impact from endogenous substances (hemoglobin, bilirubin, lipids, HAMA, etc.) or common therapeutic drugs.

Technological Characteristics

Two-reagent competitive immunoassay. Reagents: vancomycin conjugate, PIPES buffer, anti-vancomycin antibody (mouse monoclonal), latex microparticles, MOPS buffer. Measuring range: 4.0–80.0 μg/mL. Instrumentation: Roche/Hitachi cobas c 501. Connectivity: Automated clinical chemistry analyzer. Sterilization: N/A (reagents). Standards: CLSI EP5-A2, EP6-A, EP17-A, EP7-A2, EP9-A2.

Indications for Use

Indicated for patients requiring quantitative measurement of vancomycin in serum or plasma to monitor therapeutic levels or diagnose overdose.

Regulatory Classification

Identification

A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.

Predicate Devices

• ONLINE TDM Vancomycin (k060586)

Submission Summary (Full Text)

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

January 8, 2016

ROCHE DIAGNOSTICS OPERATIONS (RDO) BARBARA MCWHORTER REGULATORY AFFAIRS PRINCIPAL 9115 HAGUE ROAD INDIANAPOLIS IN 46250

Re: K152245

Trade/Device Name: ONLINE TDM Vancomvcin Gen.3 Regulation Number: 21 CFR 862.3950 Regulation Name: Vancomycin test system Regulatory Class: II Product Code: LEH Dated: December 9, 2015 Received: December 10, 2015

Dear Barbara Mc Whorter:

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 Parts 801 and 809); 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.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number [phone] or [phone] or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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 Industry and Consumer Education at its toll-free number [phone] or [phone] or at its Internet address

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

Sincerely yours.

Courtney H. Lias -S

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) K152245

Device Name ONLINE TDM Vancomycin Gen.3

#### Indications for Use (Describe)

In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems.

A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.

Type of Use (Select one or both, as applicable)

| <div> <span> <span style="font-size: 20px;">☑</span> Prescription Use (Part 21 CFR 801 Subpart D) </span> </div> |
|------------------------------------------------------------------------------------------------------------------------------------------------------|
| <div> <span> ☐ Over-The-Counter Use (21 CFR 801 Subpart C) </span> </div> |

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# 510(k) Summary

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

| Submitter Name | Roche Diagnostics Operations (RDO) |
|-------------------------------|---------------------------------------------------------------------------------------------------------|
| Address | 9115 Hague Road<br>Indianapolis, IN, 46250, USA |
| Contact | Barbara McWhorter<br>Phone: [phone]<br>FAX: [phone]<br>Email: [e-mail] |
| Date Prepared | July 31st, 2015 |
| Proprietary Name | ONLINE TDM Vancomycin Gen.3 |
| Common Name | Immunoassay, Vancomycin |
| Classification Name | Clinical Toxicology Test Systems, Class II |
| Product Codes | LEH, 21 CFR § 862.3950 |
| Predicate Devices | ONLINE TDM Vancomycin, K060586 |
| Establishment<br>Registration | 1823260, Roche Diagnostics Operations Inc. |

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#### 1. DEVICE DESCRIPTION

The ONLINE TDM Vancomycin Gen.3 is a two reagent assay for the in vitro quantitative determination of vancomycin in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles in solution (KIMS). A competitive reaction takes place between the drug conjugate and vancomycin in the serum sample for binding to the vancomycin antibody on the microparticles. The resulting kinetic interaction of microparticles is indirectly proportional to the amount of drug present in the sample.

#### 2. INDICATIONS FOR USE

In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems.

A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.

#### 3. TECHNOLOGICAL CHARACTERISTICS

The assay is based on the kinetic interaction of microparticles in a solution (KIMS). Vancomycin antibody is covalently coupled to microparticles and the drug derivative is linked to a macromolecule. The kinetic interaction of microparticles in solutions is induced by binding of drug-conjugate to the antibody on the microparticles and is inhibited by the presence of Vancomycin in the sample. A competitive reaction takes place between the drug conjugate and Vancomycin in the serum sample for binding to the Vancomycin antibody on the microparticles. The resulting kinetic interaction of microparticles is indirectly proportional to the amount of drug present in the sample.

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Reagents - working solutions:

- . R1 Vancomycin conjugate; piperazine-N,N-bis (2-ethanesulfonic acid) (PIPES) buffer, pH 7.2; preservative; stabilizer
- R2 Anti-Vancomycin antibody (mouse monoclonal); latex microparticle; 3 -(Nmorpholino) propane sulfonic acid (MOPS) buffer, pH 7.2; stabilizer

#### 4. PREDICATE DEVICE

The predicate device, manufactured by Siemens, which Roche Diagnostics claims substantial equivalence to, is the ONLINE TDM Vancomycin assay. This was cleared in k060586 as a Traditional 510(k) on the Roche/Hitachi 917 and Modular P analyzer systems. The ONLINE TDM Vancomycin assay was then applied to the cobas c 501 analyzer system. FDA designated this CLIA categorization as moderate complexity with the k060373/A001.The following table compares the features of the candidate device to the predicate device.

| Assay Comparison | | |
|---------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Feature | Predicate Device:<br>ONLINE TDM Vancomycin<br>K060586 | Candidate Device:<br>ONLINE TDM Vancomycin<br>Gen.3 |
| Intended Use | The ONLINE TDM Vancomycin<br>assay is for the quantitative<br>determination of vancomycin in<br>human serum or plasma on Roche<br>automated clinical chemistry<br>analyzers. | In vitro test for the quantitative<br>determination of vancomycin in<br>serum and plasma on<br>Roche/Hitachi cobas c systems. |
| Analyzer Systems | Hitachi / Roche Modular P and 917<br>cobas c 501 (k060373/A001) | cobas c 501 |
| Sample Types | Serum: Collect serum using<br>standard sampling tubes.<br>Plasma:Potassium (K2 or K3)<br>EDTA,sodium citrate, or fluoride<br>oxalate plasma. | Serum<br>Plasma: K2- or K3-EDTA, lithium<br>heparin. |
| Assay Comparison | | |
| Feature | Predicate Device:<br>ONLINE TDM Vancomycin<br>K060586 | Candidate Device:<br>ONLINE TDM Vancomycin<br>Gen.3 |
| Test Principle | The assay is based on a<br>homogeneous enzyme immunoassay<br>technique used for the quantitative<br>analysis of vancomycin in human<br>serum or plasma. The assay is based<br>on competition between drug in the<br>sample and drug labeled with the<br>enzyme glucose-6-phosphate<br>dehydrogenase (G6PDH) for<br>antibody binding sites. Enzyme<br>activity decreases upon binding to<br>the antibody, so the drug<br>concentration in the sample can be<br>measured in terms of enzyme<br>activity. Active enzyme converts<br>oxidized nicotinamide adenine<br>dinucleotide (NAD) to NADH,<br>resulting in an absorbance change<br>that is measured<br>spectrophotometrically. Endogenous<br>serum G6PDH does not interfere<br>because the coenzyme functions<br>only with the bacterial (Leuconostoc<br>mesenteroids) enzyme employed in<br>the assay. | The assay is based on the kinetic<br>interaction of microparticles in a<br>solution (KIMS). Vancomycin<br>antibody is covalently coupled to<br>microparticles and the drug<br>derivative is linked to a<br>macromolecule. The kinetic<br>interaction of microparticles in<br>solutions is induced by binding of<br>drug-conjugate to the antibody on<br>the microparticles and is inhibited<br>by the presence of Vancomycin in<br>the sample. A competitive reaction<br>takes place between the drug<br>conjugate and Vancomycin in the<br>serum sample for binding to the<br>Vancomycin antibody on the<br>microparticles. The resulting<br>kinetic interaction of<br>microparticles is indirectly<br>proportional to the amount of drug<br>present in the sample. |
| Reagent Shelf Life<br>Stability | 2-8 °C until expiration date | Same |
| Reagent On-Board<br>Stability | 60 days opened and refrigerated on<br>the analyzer. Do not freeze. | 12 weeks on-board in use and<br>refrigerated on the analyzer. Do<br>not freeze. |
| Measuring Range | 1.7 to 80 µg/mL<br>(based on LDL) | 4.0 to 80 µg/mL<br>(based on LoQ) |
| Traceability | This method has been standardized<br>against USP reference standards. | Same |
| Calibrator | Preciset TDM 1 calibrator<br>(Previously cleared 510(k):<br>k031856) | Same |
| Calibration<br>Frequency | • after reagent bottle change<br>• after reagent lot change<br>• as required following quality<br>control procedures | • after lot change<br>• after 6 weeks<br>• as required following quality<br>control procedures |
| Controls | TDM Control Set<br>(Previously cleared 510(k): k060429<br>and k070200) | Same |
| Assay Comparison | | |
| Feature | Predicate Device:<br>ONLINE TDM Vancomycin<br>K060586 | Candidate Device:<br>ONLINE TDM Vancomycin<br>Gen.3 |
| Lower Limits of<br>Measurement | Lower Detection Limit = 1.7<br>µg/mL (1.2 µmol/L) | LoB = 1.0 µg/mL (0.69 µmol/L)<br>LoD = 1.5 µg/mL (1.04 µmol/L)<br>LoQ = 4.0 µg/mL (2.76 µmol/L) |
| Reagent<br>Composition | R1 Enzyme Reagent<br>Vancomycin labeled with bacterial<br>G6PHDH in buffer<br>R2 Antibody/Substrate Reagent<br>Anti-vancomycin antibody (mouse<br>monoclonal), G6P and NAD in<br>buffer | R1 Vancomycin conjugate;<br>piperazine-N,N'-bis (2<br>ethanesulfonic acid) (PIPES)<br>buffer, pH 7.2; preservative;<br>stabilizer<br>R2 Anti-Vancomycin antibody<br>(mouse monoclonal); latex<br>microparticle; 3-(N-morpholino)<br>propane sulfonic acid (MOPS)<br>buffer, pH 7.2; stabilizer |

### Table 1: Substantial Equivalence – Assav Comparison

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#### 5. NON-CLINICAL PERFORMANCE EVALUATION

The following performance data were provided in support of the substantial equivalence determination:

Detection Limit: LoB, LoD and LoQ according to CLSI EP17-A2

Precision according to CLSI EP5-A2

Linearity according to CLSI EP6-A

Matrix Comparison - Anticoagulants

Interferences - H, L and I Indices

Interference - Drugs

Method Comparison to Predicate

#### 5.1. Detection Limit

LoB, LoD, and LoQ studies were performed based upon CLSI EP17-A2.

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### LoB:

LoB (Limit of Blank) corresponds to the concentration below which analyte-free samples are found with a probability of 95%.

For MP Lot: The diluent is measured with 5-fold determinations per run on two instruments. Six runs distributed over 3 days were performed. Data analysis was based on determination of the 95th percentile of the 60 measured values.

For P2 and P3 Lots: The diluent is measured with 5-fold determinations per run on one instrument. Six runs distributed over 3 days were performed. Data analysis was based on determination of the 95th percentile of the 60 measured values.

### LoD:

LoD (Limit of Detection) corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95 %).

For MP Lot: Five serum samples with low analyte content spiked with Vancomycin (with concentrations ranging from LoB to approx. 4 times specified LoB) were measured with 1-fold determination per run on two instruments. Six runs distributed over 3 days were performed.

For P2 and P3 Lots: Five serum samples with low analyte content spiked with Vancomycin (with concentrations ranging from LoB to approx. 4 times specified LoB) were measured with 2-fold determination per run on one instrument. Six runs distributed over 3 days were performed.

### LoQ:

LoQ (Limit of Quantitation) is the lowest amount of analyte in a sample that can be detected quantitatively within specified precision and accuracy ranges.

Fifteen serum samples were prepared which cover the concentration range between LoB and 2x LoQ. Those samples were tested in two aliquots. Six runs over 4 days were performed. Expected value is determined with Vancomycin LCMS/MS.

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| | Result MP Lot<br>(μg/mL) | Result P2 Lot<br>(μg/mL) | Result P3 Lot<br>(μg/mL) | Claim<br>(μg/mL) |
|-----------------------------|--------------------------|--------------------------|--------------------------|------------------|
| Limit of Blank (LoB) | 0.6 | 0.7 | 0.5 | 1.0 |
| Limit of Detection (LoD) | 1.4 | 1.3 | 1.1 | 1.5 |
| Limit of Quantitation (LoQ) | 2.0 | 3.3 | 3.1 | 4.0 |

## Table 2: LoB, LoD, and LoQ Experimental Determination

#### 5.2. Precision according to CLSI EP5-A

Precision experiments were performed in Accordance with CLSI Guideline EP5-A2. Two runs per day for $\geq$ 21 days were performed on the same analyzer. Repeatability and intermediate precision was calculated. The serum samples were randomized in each run separately. The data set was completed for the 21 days. For each sample, the following were calculated: Mean, Repeatability and Intermediate precision as CV and SD values.

| Specimen | Mean (µg/mL) | SD (µg/mL) | CV (%) |
|---------------|--------------|------------|--------|
| TDM Control 1 | 7.45 | 0.4 | 5.2 |
| TDM Control 2 | 21.5 | 0.5 | 2.3 |
| TDM Control 3 | 36.2 | 0.9 | 2.4 |
| Human Serum 1 | 4.82 | 0.4 | 8.2 |
| Human Serum 2 | 7.95 | 0.4 | 5.2 |
| Human Serum 3 | 32.1 | 0.8 | 2.5 |
| Human Serum 4 | 40.0 | 1.0 | 2.5 |
| Human Serum 5 | 71.4 | 2.0 | 2.8 |

### Table 3: Repeatability Precision Summary

### Table 4: Intermediate Precision Summary

| Specimen | Mean ( $\mu$ g/mL) | SD ( $\mu$ g/mL) | CV (%) |
|---------------|--------------------|------------------|--------|
| TDM Control 1 | 7.45 | 0.5 | 6.2 |
| TDM Control 2 | 21.5 | 0.8 | 3.7 |
| TDM Control 3 | 35.5 | 1.1 | 3.2 |
| Human Serum 1 | 4.93 | 0.5 | 10.5 |
| Human Serum 2 | 7.95 | 0.5 | 5.9 |
| Human Serum 3 | 32.1 | 1.1 | 3.4 |
| Human Serum 4 | 39.5 | 1.1 | 2.9 |
| Human Serum 5 | 71.4 | 2.2 | 3.1 |

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#### Linearity according to CLSI EP6-A 5.3.

A dilution series were prepared from a human serum sample pool and diluent (Preciset TDM1Diluent). The dilution series were prepared to obtain sixteen levels* (including the high concentration pool and diluent). The diluted samples shall span the measuring range including a non-zero sample below the measuring range and a sample over the measuring range. The process was repeated for plasma samples.

* Due to the importance of the trough concentration (ca. 5 – 10 $\mu$g/mL Vancomycin) and due to the unknown LoQ before the measurement, more samples were chosen in the low concentration range.

The calculation is according to the CLSI guideline EP6-A. All measurement data of the dilution steps were calculated by linear regression without weighting.

| Sample Type | Linear Regression Equation | Claimed Measuring Range |
|-------------|--------------------------------------------------------------|-------------------------|
| Serum | y=1.000x-0.000<br>Pearson correlation coefficient (R)=0.9985 | 4.0 to 80.0 µg/mL |
| Plasma | y=1.000x-0.000<br>Pearson correlation coefficient (R)=0.9976 | 4.0 to 80.0 µg/mL |

### Table 5: Linearity Results

#### 5.4. Matrix Comparison - Anticoagulants

Each pair of serum and plasma of a single donor are spiked with Vancomycin. Included in the data are 67 full tubes and 9 half-filled tubes (except K2-EDTA plasma, which had 10 tubes). The half-filled and filled sample tubes are also from one donor. Method comparison is executed by taking the serum as reference. Only samples within the measuring range were used.

The following method comparisons are provided:

- K2-EDTA plasma vs serum ●
- K3-EDTA plasma vs serum
- Li-Heparin plasma vs serum ●

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### Table 6: Matrix Comparison

| Anticoagulant | Correlation |
|----------------------|------------------------------|
| Serum vs. Li-heparin | $y = 1.01x -0.3, r = 0.996$ |
| Serum vs. K2-EDTA | $y = 0.99x -0.0, r = 0.996$ |
| Serum vs. K3-EDTA | $y = 1.00x - 0.3, r = 0.995$ |

#### 5.5. Interferences - H, L and I Indices

The effect on quantitation of analyte in the presence of endogenous interfering substances is determined at two Vancomycin concentrations and a dilution set of the added interfering substances. Interfering substances evaluated include:

Hemolysis up to an H index of 1000

Lipemia up to an L index of 1000

Icterus/Bilirubin up to an I index of 60

High concentrated stock solutions of the interference substances were prepared in a suitable solvent. Two human serum sample pools were spiked with the defined Vancomvcin concentrations and divided into two aliquots. The potential interfering substance is added to one aliquot, while the other aliquot was mixed with the same amount of solvent without the interfering substance. A dilution series was prepared with 11 dilution steps for each interferent by mixing the 2 aliquots. Three aliquots per level were tested in 1 run on 1 instrument and 1 lot.

The parts containing the interfering substance will have the same Vancomycin concentrations as the aliquots containing no interfering substance. When diluting those two aliquots the Vancomycin concentration will remain constant while the concentration of interferent will vary. Thus the effect of increasing concentrations of interferent can be determined.

Median of the measured results were compared to the expected result (aliquot with no interfering substance) and the recovery is determined (paired difference testing).

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| Interferent | No interference up to |
|------------------------|------------------------------------------------|
| Hemolysis | Level 1: 1161 H Index<br>Level 2: 1133 H Index |
| Lipemia | Level 1: 1234 L Index<br>Level 2: 1232 L Index |
| Unconjugated Bilirubin | Level 1: 79 I Index<br>Level 2: 82 I Index |
| Conjugated Bilirubin | Level 1: 77 I Index<br>Level 2: 75 I Index |

## Table 7: Interference from Endogenous Substances

### Labeling Claim for Endogenous Substances:

### Icterus:

No significant interference up to an I index of 60 for conjugated bilirubin and unconjugated bilirubin (approximate conjugated and unconjugated bilirubin concentration: 60 mg/dL or 1026 umo1/L).

### Hemolysis:

No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 1000 mg/dL or 622 umol/L).

### Lipemia (Intralipid):

No significant interference up to an L index of 1000. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration. No significant interference from triglycerides up to 1000 mg/dL (11.4 mmol/L).

#### 5.6. Interferences – Drugs

Two human serum sample pools spiked with the defined Vancomycin concentrations were divided into two aliquots. One aliquot of each concentration were used as the reference sample for Vancomycin concentration and were not spiked with the drugs but the solvent for the drug.

The other aliquots, with either the high or low Vancomycin concentration, were spiked with the respective amount of drug. The Vancomycin concentration of the spiked aliquots were tested with 3 replicates in one run, 1 reagent lot and one instrument. The defined pharmaceutical compounds were spiked into samples with concentrations according to EP7-A2 or higher concentrations.

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| Drug | Highest Concentration Shown Not to Interfere with<br>Vancomycin |
|----------------------|-----------------------------------------------------------------|
| Acetylsalicylic acid | 1000 mg/L |
| Acetaminophen | 200 mg/L |
| Acetylcysteine | 1660 mg/L |
| Ampicillin-sodium | 1000 mg/L |
| Ascorbic acid | 300 mg/L |
| Cefoxitin | 2500 mg/L |
| Cyclosporine | 5 mg/L |
| Doxycycline | 50 mg/L |
| Heparin | 5000 U/L |
| Ibuprofen | 500 mg/L |
| Levodopa | 20 mg/L |
| Methyldopa | 20 mg/L |
| Metronidazole | 200 µg/mL |
| Methotrexate | 455 µg/mL |
| Phenylbutazone | 400 mg/L |
| Rifampicin | 60 mg/L |
| Theophyllin | 100 mg/L |

# Table 8: Common Drug Interferences

#### 5.7. Method Comparison to Predicate

One hundred twenty five single native human serum samples of patients taking Vancomycin covering the reportable range were tested. Eight of these native Vancomycin samples were spiked with Vancomycin and 1 sample diluted to cover the range. All samples were tested for icteric, lipemic and hemolytic interference.

The samples were tested in singlicate on the candidate and predicate device (cobas c 501).

The data was evaluated using Passing Bablok Regression analysis.

$$\mathbf{y} = 0.993\mathbf{x} + 0.641, \mathbf{r} = 0.994$$

#### CONCLUSIONS 6.

The submitted information in this premarket notification supports a substantial equivalence decision.