Emit II Plus Buprenorphine Assay, Emit II Plus Specialty Drug Calibrator/Control Level 1, Level 2 Level 3, Level 4, Emit II Plus Specialty Drug Control Negative, Emit II Plus Specialty Drug Control Positive

K150606 · Siemens Healthcare Diagnostics, Inc. · DJG · Oct 23, 2015 · Clinical Toxicology

Device Facts

• Record ID: K150606
• Device Name: Emit II Plus Buprenorphine Assay, Emit II Plus Specialty Drug Calibrator/Control Level 1, Level 2 Level 3, Level 4, Emit II Plus Specialty Drug Control Negative, Emit II Plus Specialty Drug Control Positive
• Applicant: Siemens Healthcare Diagnostics, Inc.
• Product Code: DJG · Clinical Toxicology
• Decision Date: Oct 23, 2015
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3650
• Device Class: Class 2

Indications for Use

Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay with a 5 ng/mL cutoff. The assay is intended for use in laboratories for the qualitative and/or semi-quantitative analyses of buprenorphine in human urine. Emit® II Plus assays are designed for use with a number of chemistry analyzers. The semi-quantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as LC/MS or permitting laboratories to establish quality control procedures. The Emit® II Plus Buprenorphine Assay provides only a preliminary analytical test result. A more specific alternative chemical method(s) must be used to obtain a confirmed analytical result. GC/MS and LC/MS are the preferred confirmatory methods. Other chemical confirmation methods are available. Clinical consideration and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Emit® II Plus Specialty Drug Calibrator/Control Level 1, Emit® II Plus Specialty Drug Calibrator/Control Level 2, Emit® II Plus Specialty Drug Calibrator/Control Level 3, Emit® II Plus Specialty Drug Calibrator/Control Level 4 The Emit® II Plus Specialty Drug Calibrators/Controls are used in the calibration of the Emit® II Plus Buprenorphine Assay. These products may also be used as quality control materials based on the Buprenorphine Assay cutoff. Emit® II Plus Specialty Drug Negative Control and Emit® II Plus Specialty Drug Positive Control The Emit® II Plus Specialty Drug Negative Control and Emit® II Plus Specialty Drug Positive Control are for use with the Emit® II Plus Buprenorphine Assay.

Device Story

Homogeneous enzyme immunoassay for buprenorphine detection in human urine; utilizes two-reagent system (mouse monoclonal antibodies, G6P, NAD, and norbuprenorphine-labeled rG6PDH). Operates on automated chemistry analyzers (e.g., Viva-E®) capable of temperature control, pipetting, and spectrophotometric measurement at 340 nm. Enzyme activity inversely proportional to drug concentration; active enzyme converts NAD to NADH, causing absorbance change. Used in clinical laboratories by technicians; provides preliminary results to guide specimen dilution for confirmatory testing (LC/MS). Supports clinical decision-making regarding drug-of-abuse screening.

Clinical Evidence

No clinical studies performed. Analytical performance established via bench testing. Method comparison study evaluated 127 human urine samples against LC/MS/MS reference method, showing 90% positive agreement and 98% negative agreement. Precision studies (N=80 per level) conducted per CLSI EP5-A2. Interference testing (endogenous substances, structurally related/unrelated compounds) showed no significant interference at 5 ng/mL cutoff.

Technological Characteristics

Homogeneous enzyme immunoassay. Reagents: Mouse monoclonal antibodies, G6P, NAD, norbuprenorphine-labeled rG6PDH. Liquid, ready-to-use. Detection: Spectrophotometric absorbance change at 340 nm. Analyzers: Automated clinical chemistry systems. Standards: CLSI EP5-A2, EP17-A2, EP7-A2. Traceable to Cerilliant Buprenorphine (Cat. No. B-902).

Indications for Use

Indicated for qualitative and semi-quantitative analysis of buprenorphine in human urine in laboratory settings. Provides preliminary results requiring confirmation by GC/MS or LC/MS. Intended for use with automated chemistry analyzers.

Regulatory Classification

Identification

An opiate test system is a device intended to measure any of the addictive narcotic pain-relieving opiate drugs in blood, serum, urine, gastric contents, and saliva. An opiate is any natural or synthetic drug that has morphine-like pharmocological actions. The opiates include drugs such as morphine, morphine glucoronide, heroin, codeine, nalorphine, and meperedine. Measurements obtained by this device are used in the diagnosis and treatment of opiate use or overdose and in monitoring the levels of opiate administration to ensure appropriate therapy.

Special Controls

*Classification.* Class II (special controls). An opiate test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (*e.g.,* programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).

Predicate Devices

• Microgenics CEDIA® Buprenorphine Assay (K040316)
• Microgenics CEDIA® Buprenorphine Calibrators (K040316)
• Microgenics CEDIA® Buprenorphine Controls (K040316)

Submission Summary (Full Text)

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

A. 510(k) Number:
k150606

B. Purpose for Submission:
New device

C. Measurand:
Buprenorphine

D. Type of Test:
Qualitative and semi-quantitative immunoassay

E. Applicant:
Siemens Healthcare Diagnostics Inc.

F. Proprietary and Established Names:
Emit® II Plus Buprenorphine Assay
Emit® II Plus Specialty Drug Calibrator/Control Levels 1-4
Emit® II Plus Specialty Drug Control Negative
Emit® II Plus Specialty Drug Control Positive

G. Regulatory Information:

| Product Code | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| DJG | II | 862.3650 - Opiate test system | 91 - Toxicology |
| DLJ | II | 862.3200 - Clinical toxicology calibrator | 91 - Toxicology |
| LAS | I, reserved | 862.3280 - Clinical toxicology control material | 91 - Toxicology |

H. Intended Use:

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

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2. Indication(s) for use:

Emit® II Plus Buprenorphine Assay.

Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay with a 5 ng/mL cutoff. The assay is intended for use in laboratories for the qualitative and/or semi-quantitative analyses of buprenorphine in human urine. Emit® II Plus assays are designed for use with a number of chemistry analyzers.

The semi-quantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as LC/MS or permitting laboratories to establish quality control procedures.

The Emit® II Plus Buprenorphine Assay provides only a preliminary analytical test result. A more specific alternative chemical method(s) must be used to obtain a confirmed analytical result. GC/MS and LC/MS are the preferred confirmatory methods. Other chemical confirmation methods are available. Clinical consideration and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used.

Emit® II Plus Specialty Drug Calibrator/Control Level 1, Emit® II Plus Specialty Drug Calibrator/Control Level 2, Emit® II Plus Specialty Drug Calibrator/Control Level 3, Emit® II Plus Specialty Drug Calibrator/Control Level 4

The Emit® II Plus Specialty Drug Calibrators/Controls are used in the calibration of the Emit® II Plus Buprenorphine Assay. These products may also be used as quality control materials based on the Buprenorphine Assay cutoff.

Emit® II Plus Specialty Drug Negative Control and Emit® II Plus Specialty Drug Positive Control

The Emit® II Plus Specialty Drug Negative Control and Emit® II Plus Specialty Drug Positive Control are for use with the Emit® II Plus Buprenorphine Assay.

3. Special conditions for use statement(s):

For prescription use.

4. Special instrument requirements:

Analyzers must be capable of maintaining a constant reaction temperature, pipette specimens/reagents, mix thoroughly, measure enzyme rates precisely and time the reaction accurately. All performance studies were conducted on the Viva-E® analyzer.

I. Device Description:

The Emit® II Plus Buprenorphine assay is a homogeneous enzyme immunoassay with a 5 ng/mL cutoff. The assay, used for the detection of Buprenorphine in human urine, utilizes a

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two-reagent system. The Antibody/Substrate Reagent 1 is a liquid ready-to-use product comprised of mouse monoclonal antibodies to buprenorphine, glucose-6-phosphate (G6P), and nicotinamide adenine dinucleotide (NAD) in a diluent containing bovine serum albumin (BSA), preservatives and stabilizers. The Enzyme Reagent 2 is a liquid, ready-to-use product containing norbuprenorphine labeled bacterial recombinant glucose-6 phosphate dehydrogenase (rG6PDH) in a diluent containing bovine serum albumin (BSA), Hepes buffer, preservatives and stabilizers.

The assay kit consists of Reagent 1 and Reagent 2 in plastic containers and is available in three sizes: large kit (1L), small kit (115 mL), and 28 mL kit. Emit II Plus assays are designed for use with a number of chemistry analyzers.

The Emit® II Plus Buprenorphine assay provides only a preliminary analytical test result. A more specific alternative chemical method must be used to obtain a confirmed analytical result.

Calibrators and controls are sold separately.

## J. Substantial Equivalence Information:

1. Predicate device name(s):

Microgenics CEDIA® Buprenorphine Assay

Microgenics CEDIA® Buprenorphine Calibrators

Microgenics CEDIA® Buprenorphine Controls

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

K040316

3. Comparison with predicate:

| Similarities - Reagent | | |
| --- | --- | --- |
| Item | Predicate Device CEDIA® Buprenorphine Assay (K040316) | Proposed Device Emit® II Plus Buprenorphine Assay |
| Intended Use | A homogeneous enzyme immunoassay for qualitative or semi-quantitative determination of the presence of burprenorphine in human urine at a cutoff concentration of 5ng/mL. Preliminary analytical test result. | Same |
| Analyte | Buprenorphine | Same |

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| Similarities - Reagent | | |
| --- | --- | --- |
| Item | Predicate Device CEDIA® Buprenorphine Assay (K040316) | Proposed Device Emit® II Plus Buprenorphine Assay |
| Antibody | Mouse monoclonal antibody to buprenorphine | Same |
| Test System | Homogeneous enzyme immunoassay | Same |
| Detection | Absorbance change measured spectrophotometrically | Same |
| Sample type | Human urine | Same |
| Cutoff | 5 ng/mL | Same |
| Instrument | Automated clinical analyzers capable of maintaining a constant temperature, pipetting, mixing reagents, measuring enzymatic rates, and timing the reaction. | Same |
| Calibrator levels | 0 ng/mL + four (4) levels | Same |
| Control Positive and Control Negative Levels | High Control: 7 ng/mL Low Control: 3 ng/mL | Same |
| Differences - Reagent | | |
| --- | --- | --- |
| Item | Predicate Device CEDIA® Buprenorphine Assay (K040316) | Proposed Device Emit® II Plus Buprenorphine Assay |
| Assay methodology | Uses CEDIA® technology | Uses EMIT® technology |
| Detection | Absorbance change measured spectrophotometrically at 660 nm. | Absorbance change measured spectrophotometrically at 340 nm. |
| Reference Methodology | GC/MS | LC/MS |
| Reagents Form | R1 and R2: Lyophilized (Reconstitution Required) | R1: Liquid – Ready to use R2: Liquid – Ready to use |
| Calibrator levels | 0, 5, 20, 50, and 75 ng/mL | 0, 2.5, 5, 15, and 25 ng/mL |

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| Similarities - Calibrators | | |
| --- | --- | --- |
| Attributes | Predicate Device CEDIA® Buprenorphine Calibrator (K040316) | Proposed Device Emit® II Plus Specialty Drug Calibrator/Control |
| Intended Use | The CEDIA® Buprenorphine calibrators are used to calibrate the CEDIA® Buprenorphine Assay in human urine. | For calibration of the Emit® II Plus Buprenorphine Assay. These products may also be used as quality control materials based on the Buprenorphine Assay |
| Matrix | Human urine | Same |
| Analyte | Buprenorphine | Same |
| Target Concentrations for Buprenorphine | 0 ng/mL + four (4) levels | Same |
| Preparation | Liquid - Ready to use | Same |
| Storage | 2 – 8°C | Same |
| Differences - Calibrators | | |
| --- | --- | --- |
| Attributes | Predicate Device CEDIA® Buprenorphine Calibrator (K040316) | Proposed Device Emit® II Plus Specialty Drug Calibrator/Control |
| Target Concentration for Buprenorphine | 0, 5, 20, 50, and 75 ng/mL | 0, 2.5, 5, 15, and 25 ng/mL |
| Similarities and Differences - Controls | | |
| --- | --- | --- |
| Attributes | Predicate Device CEDIA® Buprenorphine Negative Control and Positive Control (K040316) | Proposed Device Emit® II Plus Specialty Drug Negative Control and Positive Control |
| Intended Use | The CEDIA® Buprenorphine controls are used to qualify the CEDIA® Buprenorphine Assay in human urine. | The Emit® II Plus Specialty Drug Control Negative and Control Positive are for use with the Emit® II Plus Buprenorphine Assay. |
| Matrix | Human urine | Same |
| Analyte | Buprenorphine | Same |

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| Similarities and Differences - Controls | | |
| --- | --- | --- |
| Attributes | Predicate Device CEDIA® Buprenorphine Negative Control and Positive Control (K040316) | Proposed Device Emit® II Plus Specialty Drug Negative Control and Positive Control |
| Target Concentrations for Buprenorphine | High Control: 7 ng/mL
Low Control: 3 ng/mL | Positive Control: 7 ng/mL
Negative Control: 3 ng/mL |
| Preparation | Liquid, ready to use | Same |
| Storage | 2 – 8°C | Same |

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

CLSI EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods<br/>
CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures<br/>
CLSI EP7-A2: Interference Testing in Clinical Chemistry

## L. Test Principle:

The Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay technique used for the analysis of a specific compound in human urine. The assay is based on competition between drug in the specimen and drug labeled with the recombinant glucose-6-phosphate dehydrogenase (rG6PDH) for antibody binding sites. Enzyme activity decreases upon binding to the antibody, so the drug concentration in the specimen can be measured in terms of enzyme activity. Active enzyme converts nicotinamide adenine dinucleotide (NAD) to NADH in the presence of glucose-6-phosphate (G6P), resulting in an absorbance change that is measured spectrophotometrically. Endogenous serum G6PDH does not interfere because the coenzyme NAD functions only with the bacterial (Leuconostoc mesenteroides) enzyme employed in the assay.

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

1. Analytical performance:
a. Precision/Reproducibility:

Precision studies were conducted using urine pools spiked with Buprenorphine into drug free human urine at 8 concentrations. For each level, samples were analyzed in duplicate twice a day, for 20 days (N=80). Precision data were calculated according to the Clinical and Laboratory Standards Institute (CLSI) Guidelines EP5-A2. Results are summarized in tables below:

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Qualitative Analysis

| Urine Pool (ng/mL) | % of Cutoff | # of Determinations | Results |
| --- | --- | --- | --- |
| Repeatability | | | |
| 0 | -100% | 80 | 80 Negative / 0 Positive |
| 2.50 | -50% | 80 | 80 Negative / 0 Positive |
| 3.00 | -40% | 80 | 80 Negative / 0 Positive |
| 3.75 | -25% | 80 | 80 Negative / 0 Positive |
| 5.00 | cutoff | 80 | 25 Negative / 55 Positive |
| 6.25 | +25% | 80 | 80 Positive / 0 Negative |
| 7.00 | +40% | 80 | 80 Positive / 0 Negative |
| 7.50 | +50% | 80 | 80 Positive / 0 Negative |
| 10.00 | +100% | 80 | 80 Positive / 0 Negative |
| Within-lab | | | |
| 0 | -100% | 80 | 80 Negative / 0 Positive |
| 2.50 | -50% | 80 | 80 Negative / 0 Positive |
| 3.00 | -40% | 80 | 80 Negative / 0 Positive |
| 3.75 | -25% | 80 | 80 Negative / 0 Positive |
| 5.00 | cutoff | 80 | 25 Negative / 55 Positive |
| 6.25 | +25% | 80 | 80 Positive / 0 Negative |
| 7.00 | +40% | 80 | 80 Positive / 0 Negative |
| 7.50 | +50% | 80 | 80 Positive / 0 Negative |
| 10.00 | +100% | 80 | 80 Positive / 0 Negative |

Semi-quantitative Analysis

| Urine Pool (ng/mL) | % of Cutoff | # of Determinations | Result |
| --- | --- | --- | --- |
| Repeatability | | | |
| 0 | -100% | 80 | 80 Negative / 0 Positive |
| 2.50 | -50% | 80 | 80 Negative / 0 Positive |
| 3.00 | -40% | 80 | 80 Negative / 0 Positive |
| 3.75 | -25% | 80 | 80 Negative / 0 Positive |
| 5.00 | cutoff | 80 | 25 Negative/55 Positive |
| 6.25 | +25% | 80 | 80 Positive / 0 Positive |
| 7.00 | +40% | 80 | 80 Positive / 0 Positive |
| 7.50 | +50% | 80 | 80 Positive / 0 Positive |
| 10.00 | +100% | 80 | 80 Positive / 0 Positive |

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| Urine Pool (ng/mL) | % of Cutoff | # of Determinations | Result |
| --- | --- | --- | --- |
| Within- Lab | | | |
| 0 | -100% | 80 | 80 Negative / 0 Positive |
| 2.50 | -50% | 80 | 80 Negative / 0 Positive |
| 3.00 | -40% | 80 | 80 Negative / 0 Positive |
| 3.75 | -25% | 80 | 80 Negative / 0 Positive |
| 5.00 | cutoff | 80 | 25 Negative / 55 Positive |
| 6.25 | +25% | 80 | 80 Positive / 0 Positive |
| 7.00 | +40% | 80 | 80 Positive / 0 Positive |
| 7.50 | +50% | 80 | 80 Positive / 0 Positive |
| 10.00 | +100% | 80 | 80 Positive / 0 Positive |

An additional precision study was performed using urine pools prepared by spiking Buprenorphine into drug-free human urine at one concentration level relative to the 5 ng/mL cutoff: -75% below the cutoff and +75% above the cutoff. The studies were performed on Viva-E® analyzer. The samples were analyzed in duplicate, 40 times for a total of 80 replicates.

## Qualitative Analysis

| Urine Pool (ng/mL) | % of Cutoff | # of Determinations | Results |
| --- | --- | --- | --- |
| Repeatability 1.25 | -75% | 80 | 80 Negative / 0 Positive |
| Within-Lab 8.75 | -75% | 80 | 80 Negative / 0 Positive |

## Semi-Quantitative Analysis

| Urine Pool (ng/mL) | % of Cutoff | # of Determinations | Results |
| --- | --- | --- | --- |
| Repeatability 1.25 | -75% | 80 | 80 Positive / 0 Positive |
| Within-Lab 8.75 | -75% | 80 | 80 Positive / 0 Positive |

## b. Linearity/assay reportable range:

Drug free urine pools were spiked with eight concentrations of buprenorphine at levels 2-25 ng/mL and analyzed semi-quantitatively in five replicates on a Viva-E® analyzer. The mean observed Buprenorphine concentration was compared to the expected Buprenorphine concentration and percent recovery results shown in the table below:

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| Expected Buprenorphine Concentration (ng/mL) | Mean Buprenorphine Concentration by Emit® II Plus Buprenorphine Assay (ng/mL) | % Recovery |
| --- | --- | --- |
| 2 | 2.1 | 105.0 |
| 3 | 3.1 | 103.3 |
| 4 | 3.9 | 97.5 |
| 5 | 5.0 | 100.0 |
| 8 | 7.7 | 96.3 |
| 12 | 11.1 | 92.5 |
| 18 | 17.7 | 98.3 |
| 22 | 21.0 | 95.5 |
| 25 | 23.9 | 95.6 |

c. Traceability, Stability, Expected values (controls, calibrators, or methods):
Emit® II Plus Specialty Drug Calibrator/Control is traceable to Cerilliant Buprenorphine Cat. No. B-902. This stock solution is used directly to prepare Master pools. The secondary stock solution is then spiked into the calibrators and controls to the desired concentration. The concentrations are confirmed by LC/MS/MS.

**Stability Studies:**
Real time and on-board stability studies for both controls and calibrators were conducted. Protocols and acceptance criteria were reviewed and found to be acceptable. The manufacturer claims the following expiration date for both controls and calibrators:
Real-time stability studies show that when stored at 2-8 °C, open and unopened product is stable for nine months. Real time stability studies are on-going to support a 12 month shelf life stability claim.
Testing supports on-board storage stability of over 30 days.

d. Detection limit:
Not applicable

e. Analytical specificity:

**Buprenorphine Metabolite Recovery:**
Buprenorphine and the buprenorphine metabolites norbuprenorphine, buprenorphine glucuronide and norbuprenorphine glucuronide were spiked into aliquots of drug free urine at the levels shown and run at N=5 replicates. The samples were assayed and the mean recovery results were determined.

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Buprenorphine and Buprenorphine Metabolite Recovery

| Compound | Conc. Tested (ng/mL) | % Cross-reactivity |
| --- | --- | --- |
| Buprenorphine | 5 | 103 |
| Norbuprenorphine | 5 | 92 |
| Buprenorphine Glucuronide | 1000 | 0.09 |
| Norbuprenorphine Glucuronide | 1000 | 0.12 |

**Structurally Related Compounds:**

Samples were prepared by spiking drug-free human urine with individual cross-reactants to the targeted level. The samples were evaluated on the Viva-E® analyzer. All samples were tested in replicates of N=5.

Cross-Reactivity with the Structurally Related Drugs

| Compound | Conc. Tested (ng/mL) | Qual. Result (Neg/Pos) | Semi-quant. Result (Neg/Pos) | % Cross-reactivity |
| --- | --- | --- | --- | --- |
| 6-acetylcodeine | 100000 | Neg | Neg | <0.01 |
| 6-acetylmorphine | 100000 | Neg | Neg | <0.01 |
| Codeine | 100000 | Neg | Neg | <0.01 |
| Dextromethorphan | 100000 | Neg | Neg | <0.01 |
| Dihydrocodeine | 100000 | Neg | Neg | <0.01 |
| Ethyl Morphine | 100000 | Neg | Neg | <0.01 |
| Heroin | 100000 | Neg | Neg | <0.01 |
| Hydrocodone | 100000 | Neg | Neg | <0.01 |
| Hydromorphone | 100000 | Neg | Neg | <0.01 |
| Levorphanol | 100000 | Neg | Neg | <0.01 |
| Morphine | 100000 | Neg | Neg | <0.01 |
| Morphine 3-glucuronide | 100000 | Neg | Neg | <0.01 |
| Morphine 6-glucuronide | 100000 | Neg | Neg | <0.01 |
| Nalorphine | 100000 | Neg | Neg | <0.01 |
| Naloxone | 100000 | Neg | Neg | <0.01 |
| Naltrexone | 100000 | Neg | Neg | <0.01 |
| Norcodeine | 100000 | Neg | Neg | <0.01 |
| Normorphine | 100000 | Neg | Neg | <0.01 |
| Noroxycodone | 100000 | Neg | Neg | <0.01 |
| Noroxymorphone | 100000 | Neg | Neg | <0.01 |
| Oxycodone | 100000 | Neg | Neg | <0.01 |
| Oxymorphone | 100000 | Neg | Neg | <0.01 |

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# Structurally Unrelated Compounds:

The following structurally unrelated compounds were added into drug-free urine spiked into two levels of controls at $\pm 40\%$ of the cutoff concentration. The substances listed in the table below do not yield a false response relative to the cutoff in both qualitative and semi-quantitative mode.

| Interference (Structurally Unrelated Compounds) | Conc. Tested (μg/mL) | - 40% Cutoff (3 ng/mL) | | +40% Cutoff (7 ng/mL) | |
| --- | --- | --- | --- | --- | --- |
| | | Qualit. Result Pos/ Neg | Semi-quant. Result Pos/ Neg | Qualit. Result Pos/ Neg | Semi-quant. Result Pos/ Neg |
| 10, 11-dihydrocarbamazepine | 85 | Neg | Neg | Pos | Pos |
| Acetaminophen | 1000 | Neg | Neg | Pos | Pos |
| Acetylsalicylic Acid | 1500 | Neg | Neg | Pos | Pos |
| Amitriptyline | 100 | Neg | Neg | Pos | Pos |
| Amoxicillin | 500 | Neg | Neg | Pos | Pos |
| ZT (Zidovudine) | 2000 | Neg | Neg | Pos | Pos |
| Benzoylecgonine | 1000 | Neg | Neg | Pos | Pos |
| Brompheniramine | 75 | Neg | Neg | Pos | Pos |
| Caffeine | 1000 | Neg | Neg | Pos | Pos |
| Captopril | 500 | Neg | Neg | Pos | Pos |
| Chlordiazepoxide | 100 | Neg | Neg | Pos | Pos |
| Chlorpromazine | 10 | Neg | Neg | Pos | Pos |
| Cimetidine | 1000 | Neg | Neg | Pos | Pos |
| Clomipramine | 2.5 | Neg | Neg | Pos | Pos |
| Clonidine | 1000 | Neg | Neg | Pos | Pos |
| Cyclobenzaprine | 125 | Neg | Neg | Pos | Pos |
| d-amphetamine | 700 | Neg | Neg | Pos | Pos |
| Desipramine | 800 | Neg | Neg | Pos | Pos |
| Diazepam | 100 | Neg | Neg | Pos | Pos |
| Digoxin | 0.01 | Neg | Neg | Pos | Pos |
| Diphenhydramine | 1000 | Neg | Neg | Pos | Pos |
| d-methamphetamine | 500 | Neg | Neg | Pos | Pos |
| Doxepine | 100 | Neg | Neg | Pos | Pos |
| EDDP | 1000 | Neg | Neg | Pos | Pos |
| EMDP | 100 | Neg | Neg | Pos | Pos |
| Enalapril | 500 | Neg | Neg | Pos | Pos |
| Fluoxetine | 500 | Neg | Neg | Pos | Pos |
| Glutethimide | 500 | Neg | Neg | Pos | Pos |
| Haloperidol | 100 | Neg | Neg | Pos | Pos |
| Hydroxyzine | 500 | Neg | Neg | Pos | Pos |
| Ibuprophen | 1000 | Neg | Neg | Pos | Pos |
| Imipramine | 200 | Neg | Neg | Pos | Pos |

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| Interference
(Structurally Unrelated Compounds) | Conc. Tested
(μg/mL) | - 40% Cutoff (3 ng/mL) | | +40% Cutoff (7 ng/mL) | |
| --- | --- | --- | --- | --- | --- |
| | | Qualit. Result
Pos/ Neg | Semi-quant. Result
Pos/ Neg | Qualit. Result
Pos/ Neg | Semi-quant. Result
Pos/ Neg |
| Ketamine | 100 | Neg | Neg | Pos | Pos |
| Ketorolac Tromethamine | 400 | Neg | Neg | Pos | Pos |
| LAAM (L-a-acetylmethadol) | 25 | Neg | Neg | Pos | Pos |
| L-Cotinine | 100 | Neg | Neg | Pos | Pos |
| Levofloxacin | 100 | Neg | Neg | Pos | Pos |
| Levothyroxine (L-Thyroxine) | 50 | Neg | Neg | Pos | Pos |
| Lidocaine | 1000 | Neg | Neg | Pos | Pos |
| Lormetazepam | 1 | Neg | Neg | Pos | Pos |
| LSD | 10 | Neg | Neg | Pos | Pos |
| MDMA (Ecstasy) | 1000 | Neg | Neg | Pos | Pos |
| Meperidine | 800 | Neg | Neg | Pos | Pos |
| Methadone | 500 | Neg | Neg | Pos | Pos |
| Methaqualone | 600 | Neg | Neg | Pos | Pos |
| NAPA | 400 | Neg | Neg | Pos | Pos |
| Naproxen | 1000 | Neg | Neg | Pos | Pos |
| Nicotinic Acid | 500 | Neg | Neg | Pos | Pos |
| Nifedipine | 500 | Neg | Neg | Pos | Pos |
| Nordiazepam | 100 | Neg | Neg | Pos | Pos |
| Nortryptiline | 250 | Neg | Neg | Pos | Pos |
| Oxazepam | 300 | Neg | Neg | Pos | Pos |
| Perphenazine | 150 | Neg | Neg | Pos | Pos |
| Phencyclidine | 900 | Neg | Neg | Pos | Pos |
| Phenobarbital | 500 | Neg | Neg | Pos | Pos |
| Phenelzine | 100 | Neg | Neg | Pos | Pos |
| Phenytoin | 1000 | Neg | Neg | Pos | Pos |
| Procainamide | 1000 | Neg | Neg | Pos | Pos |
| Procyclidine | 800 | Neg | Neg | Pos | Pos |
| Promethazine | 100 | Neg | Neg | Pos | Pos |
| Propoxyphene | 1000 | Neg | Neg | Pos | Pos |
| Protriptyline | 200 | Neg | Neg | Pos | Pos |
| Pseudoephedrine | 1000 | Neg | Neg | Pos | Pos |
| Quinacrine | 900 | Neg | Neg | Pos | Pos |
| Ranitidine | 1000 | Neg | Neg | Pos | Pos |
| Ritalin | 1000 | Neg | Neg | Pos | Pos |
| Salicylic Acid | 500 | Neg | Neg | Pos | Pos |
| Scopolamine | 500 | Neg | Neg | Pos | Pos |
| Secobarbital | 1000 | Neg | Neg | Pos | Pos |

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| Interference (Structurally Unrelated Compounds) | Conc. Tested (μg/mL) | -40% Cutoff (3 ng/mL) | | +40% Cutoff (7 ng/mL) | |
| --- | --- | --- | --- | --- | --- |
| | | Qualit. Result Pos/ Neg | Semi-quant. Result Pos/ Neg | Qualit. Result Pos/ Neg | Semi-quant. Result Pos/ Neg |
| Tapentadol | 100 | Neg | Neg | Pos | Pos |
| THC | 100 | Neg | Neg | Pos | Pos |
| Thioridazine | 100 | Neg | Neg | Pos | Pos |
| Tramadol | 1000 | Neg | Neg | Pos | Pos |
| Trazodone | 5 | Neg | Neg | Pos | Pos |
| Trimethoprim | 1000 | Neg | Neg | Pos | Pos |
| Triprolidine (zymine) | 50 | Neg | Neg | Pos | Pos |
| Tyramine | 100 | Neg | Neg | Pos | Pos |
| Verapamil | 500 | Neg | Neg | Pos | Pos |
| Zolpidem | 100 | Neg | Neg | Pos | Pos |

## Endogenous Substances Interference:

Each compound was spiked into a -40% cutoff and a +40% cutoff concentration pool which were prepared by spiking buprenorphine to aliquots of drug-free human urine. The results show that the tested endogenous substances at the levels tested caused no interference relative to the 5 ng/mL cutoff. Qualitative and semi-quantitative results are provided in the table below.

| Interferences (Endogenous Substances) | Conc. Tested | -40% Cutoff (3 ng/mL) | | +40% Cutoff (7 ng/mL) | |
| --- | --- | --- | --- | --- | --- |
| | | Qualit. Result (Pos/Neg) | Semi-Quant. Result (Pos/ Neg) | Qualit. Result (Pos/Neg) | Semi-Quant. Result (Pos/Neg) |
| Acetone | 1.0 g/dL | Neg | Neg | Pos | Pos |
| Ascorbic Acid | 1.5 g/dL | Neg | Neg | Pos | Pos |
| Conjugated Bilirubin | 2.0 mg/dL | Neg | Neg | Pos | Pos |
| Unconjugated Bilirubin | 2.0 mg/dL | Neg | Neg | Pos | Pos |
| Creatinine | 0.5 g/dL | Neg | Neg | Pos | Pos |
| Ethanol | 1.0 g/dL | Neg | Neg | Pos | Pos |
| Immuno Gamma Globulin (IgG) | 0.5 g/dL | Neg | Neg | Pos | Pos |
| Glucose | 2.0 g/dL | Neg | Neg | Pos | Pos |
| Galactose | 1.0 g/dL | Neg | Neg | Pos | Pos |
| Hemoglobin | 115 mg/dL | Neg | Neg | Pos | Pos |
| Human Serum Albumin | 0.5 g/dL | Neg | Neg | Pos | Pos |
| Oxalic Acid | 0.1 g/dL | Neg | Neg | Pos | Pos |
| Riboflavin | 7.5 mg/dL | Neg | Neg | Pos | Pos |

{13}

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| Interferences (Endogenous Substances) | Conc. Tested | -40% Cutoff (3 ng/mL) | | +40% Cutoff (7 ng/mL) | |
| --- | --- | --- | --- | --- | --- |
| | | Qualit. Result (Pos/Neg) | Semi-Quant. Result (Pos/ Neg) | Qualit. Result (Pos/Neg) | Semi-Quant. Result (Pos/Neg) |
| Sodium Chloride | 6.0 g/dL | Neg | Neg | Pos | Pos |
| Urea | 6.0 g/dL | Neg | Neg | Pos | Pos |
| Sodium Azide | 1% w/v | Neg | Neg | Pos | Pos |
| Sodium Fluoride | 1% w/v | Neg | Neg | Pos | Pos |

**Specific Gravity and pH:**

Negative urine pools with specific gravity values ranging from 1.002–1.035 and pH values ranging from 3.0–11.0 were tested in the presence of two levels of controls at +/- 40% (3 and 7 ng/mL) of the cutoff concentration. All samples were tested in triplicates and no interference was observed.

**f. Assay cut-off:**

Analytical performance of the device around the claimed cutoff is described in precision section (1 a.) above.

**2. Comparison studies:**

**a. Method comparison with predicate device:**

One-hundred twenty seven (127) unaltered human urine samples were qualitatively and semiquantitatively evaluated using the Emit® II Plus Buprenorphine Assay on the Viva-E® analyzer and compared with the results obtained by the reference method – LC/MS/MS. Two replicates were run on each sample on one reagent lot. The results are presented below:

Emit® II Plus Buprenorphine Assay vs. LC/MS/MS

Comparison Table for Qualitative and Semi-quantitative Assay Performance

| | LC/MS/MS | | | | % Agreement |
| --- | --- | --- | --- | --- | --- |
| | Negative (<2.5 ng/mL) | Negative Within 50% below the cutoff (2.5-4.9 ng/mL) | Positive Within 50% above the cutoff (5.0-7.5 ng/mL) | Positive (>7.5 ng/mL) | |
| Qualitative | | | | | |
| Emit® Positive | 0 | 7 | 16 | 49 | 90% |
| Emit® Negative | 45 | 9 | 1 | 0 | 98% |
| Semi-quantitative | | | | | |
| Emit® Positive | 0 | 7 | 16 | 49 | 90% |

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| Emit® Negative | 45 | 9 | 1 | 0 | 98% |
| --- | --- | --- | --- | --- | --- |

Discordant Result Summary

| Sample ID | LC/MS/MS | | Emit +/- |
| --- | --- | --- | --- |
| | Bup (ng/mL) | NorBup (ng/mL) | |
| 190 | 0 | 3.92 | + |
| 193 | 0 | 4.97 | + |
| 195 | 0 | 4.06 | + |
| 226 | 0 | 4.21 | + |
| 250 | 0 | 4.13 | + |
| 77 | 0 | 4.60 | + |
| 316 | 0 | 3.86 | + |
| 338 | 5.12 | 0 | - |

Bup = Buprenorphine; NorBup = Norbuprenorphine

b. Matrix comparison:
Test is for urine samples only.

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:
Not applicable.

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.