The 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 semiquantitative analyses of buprenorphine in human urine. Emit® II Plus assays are designed for use with a number of chemistry analyzers.

The semiquantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as Liquid Chromatography/Mass Spectrometry (LC/MS) or permitting laboratories to establish quality control procedures.

The Emit® II Plus Burrenorphine Assay provides only a preliminary analytical test result. A more specific alternative chemical method(s) must be used to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry (GC/ MS) or 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.

For Professional Use.

Caution: Federal (USA) law restricts this device to sale by or on the order of a licensed healthcare professional.

For in vitro diagnostic use.

Device Description

The Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay technique used for the analysis of specific compounds 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-6phosphate (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.

The Emit® II Plus Buprenorphine Assay reagents are provided liquid, ready to use and may be used directly from the refrigerator. The product is sold in three (3) kit sizes: 28 mL, 115 mL, and 1000 mL. Reagents 1 and 2 are provided as a matched set. They should not be interchanged with components of kits with different lot numbers.

Antibody/Substrate Reagent 1: Mouse monoclonal antibodies to buprenorphine (0.53 µg/mL)*.NAD (6.9 mM), G6P (10.9 mM), bovine serum albumin, preservatives, and stabilizers. *The antibody titer and enzyme conjugate activity may vary from lot to lot.

Enzyme Reagent 2: Norbuprenorphine labeled with bacterial rG6PDH (0.50 µg/mL), HEPES buffer, bovine serum albumin, preservatives, and stabilizers, where the antibody titer and enzyme conjugate activity may vary from lot to lot.

AI/ML Overview

The marketing submission for the Siemens Healthineers Emit® II Plus Buprenorphine Assay (K221605) demonstrates that the device meets its acceptance criteria through various performance studies. Below is a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as strict numerical thresholds in the provided document, but rather demonstrated through the qualitative agreement and recovery percentages, as well as precision and specificity profiles. Based on the "Method Comparison" results, the implicit acceptance criterion for qualitative agreement against LC/MS/MS is a high percentage, and for recovery, it's generally close to 100%. For specificity, it's low or negligible cross-reactivity with other substances (ideally less than the cutoff concentration when tested at high concentrations). For precision, it's low coefficient of variation (CV).

Metric / Acceptance Criteria	Reported Device Performance (Emit® II Plus Buprenphine Assay on DxC 500 AU)
Method Comparison (Qualitative Agreement with LC/MS/MS)	92.5% Agreement
Recovery vs Nominal Value	Ranges from 95% to 104% (average ~98.5%)
Recovery vs LC/MS/MS	Ranges from 86% to 100% (average ~93.8%)
Precision (Repeatability %CV)	1.1% to 6.6% (for relevant concentration ranges)
Precision (Within-Lab Precision %CV)	2.8% to 6.6% (for relevant concentration ranges)
Total Reproducibility Precision %CV	3.0% to 5.3%
Specificity (Cross-reactivity with Buprenorphine Metabolites)	Buprenorphine: 98%, Norbuprenorphine: 106%, Glucuronides: 0.10%
Specificity (Cross-reactivity with Structurally Related Compounds)	<0.1% for all tested compounds at 100,000 ng/mL
Specificity (Cross-reactivity with Structurally Un-Related Compounds)	All tested compounds at high concentrations (µg/mL) showed 'Neg' response for the -40% Control and 'Pos' for the +40% Control, indicating no interference impacting the cutoff.
Interference (Endogenous and Exogenous Substances)	All tested substances showed 'Neg' response for the -40% Control and 'Pos' for the +40% Control, indicating no interference impacting the cutoff.
Interference (pH and Specific Gravity)	All tested pH and specific gravity levels showed 'Neg' response for the -40% Control and 'Pos' for the +40% Control, indicating no interference impacting the cutoff.

2. Sample Size Used for the Test Set and Data Provenance

Method Comparison: 120 native urine individual patient samples. The samples were collected from external suppliers, received frozen, and thawed before testing. 21% were within -50% of the cutoff and 19% within +50% of the cutoff. The provenance is not explicitly stated in terms of country of origin but implies human urine samples from external suppliers. The study design is retrospective, using previously collected samples.
Recovery: 9 urine samples prepared by spiking buprenorphine into negative urine pools.
Precision (Repeatability and Within-Lab): 11 urine samples prepared by spiking buprenorphine into negative urine pools.
Precision (Reproducibility): 3 urine samples (Negative Control, Cutoff Calibrator, Positive Control from Emit II Plus Specialty Drug Control line).
Limit of Detection: 4 blank samples and 4 low-level samples (buprenorphine spiked into drug-free urine). A minimum of 60 replicate measurements per sample set.
Specificity and Cross-reactivity: The number of unique compounds tested is substantial (listed in Tables 9, 10, and 11), with samples assayed in five replicates for each compound.
Interference: Various endogenous and exogenous substances, as well as pH and specific gravity variations, were tested at specified concentrations. Samples were assayed in five replicates.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

For the Method Comparison study, the ground truth was established by LC/MS/MS (Liquid Chromatography/Mass Spectrometry/Mass Spectrometry). This is a highly specific and sensitive analytical method considered the gold standard for drug confirmation testing. No human experts are explicitly described as establishing the ground truth; it's based on the instrumental analytical results.
For Recovery, the ground truth (nominal value) for spiked samples was determined gravimetrically based on stock concentration and confirmed by LC/MS/MS.
For Precision, Limit of Detection, Specificity, and Interference, the ground truth is based on the known concentrations of spiked substances or the known characteristics of the samples (e.g., drug-free urine, specific pH levels). Instrumental analysis is used to determine the device's measurement against these known values.

4. Adjudication Method for the Test Set

For the qualitative analysis in the Method Comparison, the results from the Emit® II Plus Buprenorphine Assay on DxC 500 AU were compared directly against the results from LC/MS/MS. A 2x2 box plot was used to assess qualitative agreement. There is no mention of a human adjudication method (e.g., 2+1 or 3+1), as the comparison is between two analytical methods.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was done. This device is an in vitro diagnostic assay, not an AI-assisted interpretation device that would involve human readers.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, the entire performance evaluation presented is a standalone study of the analytical performance of the Emit® II Plus Buprenorphine Assay on the DxC 500 AU Clinical Chemistry Analyzer. There is no human-in-the-loop component for interpreting the assay's results; the device produces qualitative or semi-quantitative analytical results directly.

7. Type of Ground Truth Used

Analytical Ground Truth:
- LC/MS/MS (Liquid Chromatography/Mass Spectrometry/Mass Spectrometry) for method comparison and as a reference for recovery studies.
- Known concentrations of spiked urine samples (gravimetrically determined nominal values) for recovery, precision, limit of detection, specificity, and interference studies. This involves preparing samples with precisely known amounts of the analyte or interfering substances.
- Drug-free urine pools for negative controls and spiking experiments.

8. Sample Size for the Training Set

The document describes performance evaluation studies for a device, not a machine learning algorithm that requires a "training set." Therefore, there is no mention of a training set or its sample size in the context of this device's regulatory submission.

9. How the Ground Truth for the Training Set Was Established

As this is not a machine learning-based device, there is no training set and thus no ground truth established for a training set. The studies focus on demonstrating the analytical performance of the immunoassay against recognized analytical standards and spiked samples with known concentrations.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA logo on the right. The FDA logo is a blue square with the letters "FDA" in white, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue.

Siemens Healthcare Diagnostics Inc. Julie Warren Regulatory Affairs Professional 500 GBC Dr. P.O. Box 6101, Mailstop 514 Newark, DE 19714

Re: K221605

Trade/Device Name: Emit® II Plus Buprenorphine Assay Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate Test System Regulatory Class: Class II Product Code: DJG Dated: March 16, 2023 Received: March 17, 2023

Dear Julie Warren:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

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for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Joseph A. Digitally signed by Kotarek -S Date: 2023.07.25

Joseph Kotarek, Ph.D. Branch Chief Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K221605

Device Name Emit® II Plus Buprenorphine Assay

Indications for Use (Describe)

For Professional Use.

Caution: Federal (USA) law restricts this device to sale by or on the order of a licensed healthcare professional.

For in vitro diagnostic use.

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

	Prescription Use (Part 21 CFR 801 Subpart D)		Over-The-Counter Use (21 CFR 801 Subpart C)
---------------	------------------------------------------------------------	---------------	-----------------------------------------------------------

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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of Safe Medical Device Act of 1990 and 21 CFR 807.92.

The assigned 510(k) number is: K221605

1. Submitter

Siemens Healthcare Diagnostics Inc. 500 GBC Dr. P.O. Box 6101 Newark, DE 19714

Primary Contact Person: Julie Warren Date of Preparation: July 7, 2023

2. Device Information

Trade Name	Emit® II Plus Buprenorphine Assay
Common Name	Buprenorphine Assay
Device	Enzyme Immunoassay, Opiates
Review Panel	Toxicology
Product Code	DJG
Submission Type	510(k)
Regulation Number	21 CFR § 862.3650
Device Class	2

3. Purpose of Submission

The purpose of this premarket notification is for the Emit® II Plus Buprenorphine Assay on the DxC 500 AU Clinical Chemistry Analyzer.

4. Predicate Device

Predicate Device Name: Emit® II Plus Buprenorphine Assay 510(k) Number: K150606

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5. Device Description

Emit® II Plus Buprenorphine Assay

Antibody/Substrate Reagent 1

Mouse monoclonal antibodies to buprenorphine (0.53 µg/mL)*.NAD (6.9 mM), G6P (10.9 mM), bovine serum albumin, preservatives, and stabilizers.

*The antibody titer and enzyme conjugate activity may vary from lot to lot.

Enzyme Reagent 2

Norbuprenorphine labeled with bacterial rG6PDH (0.50 µg/mL), HEPES buffer, bovine serum albumin, preservatives, and stabilizers, where the antibody titer and enzyme conjugate activity may vary from lot to lot.

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6. Intended Use/Indications for Use

Emit® II Plus Buprenorphine Assay

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. Gas Chromatography/Mass Spectrometry (GC/MS) or 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.

For Professional Use.

Caution: Federal (USA) law restricts this device to sale by or on the order of a licensed healthcare professional.

For in vitro diagnostic use.

7. Comparison of Technological Characteristics with the Predicate Device

The similarities and differences between the proposed device Emit II Plus Buprenorphine Assay on Beckman Coulter DxC AU 500 Clinical Chemistry Analyzer and the predicate device, Emit II Plus Buprenorphine Assay, were compared side by side.

Feature	Predicate Device:Emit II Plus BuprenorphineAssay	Proposed Device:Emit II Plus BuprenorphineAssay
Intended Use	A homogeneous enzymeimmunoassay with a 5ng/mL cutoff. The assay isintended for use inlaboratories for thequalitative and/or	Same

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Feature	Predicate Device:Emit II Plus BuprenorphineAssay	Proposed Device:Emit II Plus BuprenorphineAssay
	semiquantitative analyses ofbuprenorphine in humanurine. Preliminary analyticaltest result.
Analyte	Buprenorphine	Same
Cutoff Level	5 ng/mL	Same
Measurement	Qualitative, semi-quantitative	Same
Methodology	EMIT® technology:Homogeneous enzymeimmunoassay	Same
Detection	Absorbance changemeasuredSpectrophotometrically at340nm	Same
Instrument	Analyzers must be capableof maintaining a constantreaction temperature,pipette specimens/reagents,mix thoroughly, measureenzyme rates precisely andtime the reaction accurately.	Beckman Coulter DxC 500AU Analyzer
Sample Type	Human Urine	Same
Reagent form and storage	Liquid - ready to use, on-board storage	Same
Calibrator	0, 2.5, 5, 15, and 25 ng/mL	Same
Control Levels	Positive: 7 ng/mLNegative: 3 ng/mL	Same

8. Performance Data

The following performance studies were conducted to demonstrate substantial equivalence of the Emit II Plus Buprenorphine Assay on the DXC 500 AU Clinical Chemistry Analyzer to the Emit II Plus Buprenorphine Assay previously cleared under premarket notification 510(k), K150606.

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8.1 Method Comparison

The method comparison study was evaluated in accordance with CLSI EP09c 3rd Edition Measurement Procedure Comparison and Bias Estimation Using Patient Samples Evaluation of Precision Performance of Quantitative Measurement Methods and CLSI EP 12-A2 User Protocol for Evaluation of Qualitative Test Performance to determine accuracy and verification of the 5 ng/mL cutoff.

One hundred twenty (120) native urine individual patient samples were collected from external suppliers. The samples were received frozen, and thawed before testing. The samples were distributed across the assay range, 21% of which were within -50% of the cutoff and 19% of which were within +50% of the cutoff.

Each specimen was tested on the DxC 500 AU and on LC/MS/MS The results were analyzed using a 2x2 box plot to assess qualitative agreement relative to the 5 ng/mL cutoff value.

		LC/MS/MS
		Neg	Pos
Emit II PlusBuprenorphine on DxC500 AU	Neg	48	0
	Pos	9	63

Table 1. Method Comparison - Qualitative Analysis

Result: 92.5% Agreement

Table 2. Method Comparison - Discordant Results

SampleID	DxC500 AU(ng/mL)	Norbuprenorphine(ng/mL)	Buprenorphine+Norbuprenorphine(ng/mL)	DxC 500AUPos/Neg	LC/MS/MSPos/Neg
BUP35	6.1	4.2	4.2	Pos	Neg
BUP45	6.0	4.6	4.6	Pos	Neg
BUP51	6.1	4.3	4.3	Pos	Neg
BUP60	5.6	3.8	3.8	Pos	Neg
BUP62	6.1	3.9	3.9	Pos	Neg
BUP87	5.5	4.3	4.3	Pos	Neg
BUP95	5.6	4.5	4.5	Pos	Neg
BUP101	6.3	4.8	4.8	Pos	Neg
BUP109	5.0	4.3	4.3	Pos	Neg

Emit® II Plus Buprenorphine Assay Traditional 510(k)

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One hundred twenty (120) samples were tested. Relative to the 5 ng/mL cutoff, fortyeight (48) samples were negative by Emit II Plus Buprenorphine Assay and LC/MS/MS, and sixty-three (63) were positive. Nine (9) discordant samples were observed as positive by Emit II Plus Buprenorphine and negative by LC/MS/MS.

8.2 Recovery

The recovery was evaluated in accordance with the following testing protocol. Nine (9) urine samples were prepared by spiking buprenorphine into negative urine pools. The following levels were tested: 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, 18.0, 22.0, and 25.0 ng/mL.

Experimental design was (1) reagent lot, one (1) calibrator lot, one (1) instrument, one (1) calibration with two (2) replicate measurements each. Samples were assayed in five (5) replicates. Samples were additionally analyzed by LC/MS/MS to determine the reference value. The nominal value was determined gravimetrically based on the stock concentration.

SampleID	NominalValue(ng/mL)	DxC 500 AUValue(ng/mL)	%Recoveryvs Nominal	LC/MS/MS(ng/mL)	% RecoveryvsLC/MS/MS
BUP1	2.0	1.9	95	2.2	86
BUP2	3.0	2.9	97	3.2	91
BUP3	4.0	4.1	103	4.4	93
BUP4	5.0	4.9	98	5.1	96
BUP5	8.0	7.6	95	8.8	86
BUP6	12.0	11.6	97	13.1	89
BUP7	18.0	18.1	101	18.1	100
BUP8	22.0	22.9	104	22.9	100
BUP9	25.0	24.7	99	25.6	96

Table 3. Recovery of Emit II Plus Buprenorphine - Semi-Quantitative Analysis

8.3 Precision

Repeatability and Within-Lab Precision

The precision was evaluated in accordance with CLSI EP05-A3 Evaluation of Precision Performance of Quantitative Measurement Methods.

Eleven (11) urine samples were prepared by spiking buprenorphine into negative urine pools, aliquoted and frozen prior to the start of testing. The following levels were tested: 0, 1.25, 2.5, 3.0, 3.75, 5.0, 6.25, 7.0, 7.5, 8.75, and 10.0 ng/mL.

Experimental design was a 20x2x2 design using (1) reagent lot, one (1) calibrator lot, one (1) instrument, one (1) calibration, twenty (20) test days and two (2) runs per test

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day with two (2) replicate measurements each. Each day, two runs were performed, with a minimum of two (2) hours in between.

SampleConcentration(ng/mL)	% of theCutoff	# ofResults	Results(Pos/Neg)	Mean(mA/min)
0.0	-100%	80	80 Negative	280
1.25	-75%	80	80 Negative	297
2.5	-50%	80	80 Negative	316
3.0	-40%	80	80 Negative	323
3.75	-25%	80	80 Negative	333
5.0	0%	80	21 Negative59 Positive	363
6.25	+25%	80	80 Positive	380
7.0	+40%	80	80 Positive	392
7.5	+50%	80	80 Positive	402
8.75	+75%	80	80 Positive	427
10.0	+100%	80	80 Positive	444

Table 4. Precision of Emit II Plus Buprenorphine Qualitative Analysis

Table 5. Precision of Emit II Plus Buprenorphine Semi-Quantitative Analysis

			Repeatability		Within-Lab Precision
SampleConcentration(ng/mL)	% of theCutoff	# ofResults	Results(Pos/Neg)	Mean(ng/mL)	SD	%CV	SD	%CV
0.0	-100%	80	80 Negative	0.1	0.06	-	0.11	-
1.25	-75%	80	80 Negative	1.2	0.08	6.6	0.08	6.6
2.5	-50%	80	80 Negative	2.3	0.09	3.7	0.11	4.6
3.0	-40%	80	80 Negative	2.7	0.07	2.8	0.15	5.7
3.75	-25%	80	80 Negative	3.3	0.08	2.5	0.15	4.4
5.0	0%	80	24 Negative56 Positive	5.1	0.08	1.6	0.18	3.5
6.25	+25%	80	80 Positive	6.1	0.08	1.3	0.21	3.4
7.0	+40%	80	80 Positive	6.8	0.11	1.7	0.24	3.5
7.5	+50%	80	80 Positive	7.3	0.08	1.1	0.21	2.9
8.75	+75%	80	80 Positive	8.8	0.10	1.1	0.24	2.8
10.0	+100%	80	80 Positive	9.7	0.10	1.1	0.37	3.8

Reproducibility Precision

The reproducibility was evaluated in accordance with the following protocol.

Three (3) urine samples were tested: Emit II Plus Specialty Drug Control Negative (3 ng/mL) Emit II Plus Specialty Drug Cal/Ctrl (Cutoff Calibrator), and the Emit II Plus Specialty Drug Control Positive (7 ng/mL).

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Experimental design was a 3x5x5 design; 3 (Sites/Instruments) x 5 (replicates per day) for a total seventy-five (75) replicates per reagent lot. To capture lot-to-lot variability, three (3) Emit II Plus Buprenorphine reagent lots were processed in parallel in this study design. Testing was completed by three (3) operators. Each testing day, one (1) run was performed on three (3) instruments.

Sample	N	Mean(ng/mL)	SD	%CV
Negative Control	225	3.1	0.17	5.3
Cutoff Calibrator	225	5.0	0.18	3.7
Positive Control	225	7.1	0.21	3.0

Table 6. Total Reproducibility Precision of Emit II Plus Buprenorphine Assay

	Table 7. Reproducibility Precision of Emit II Plus Buprenorphine Assay
--	------------------------------------------------------------------------	--

			Repeatability		Between Day		Between Lot		Between Instrument/Site
Sample	N	Mean (ng/mL)	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Negative Control	225	3.1	0.11	3.6	0.06	1.8	0.03	0.8	0.11	3.4
Cutoff Calibrator	225	5.0	0.11	2.2	0.07	1.4	0.00	0.0	0.13	2.6
Positive Control	225	7.1	0.12	1.7	0.08	1.2	0.05	0.7	0.15	2.1

8.4 Limit of Detection

The limits of detection, Limit of Blank (LoB) and Limit of Detection (LoD) were evaluated in accordance with CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures.

Blank samples were drug-free negative urine, and the low samples were drug-free urine spiked with buprenorphine.

Experimental design was (2) reagent lots, one (1) calibrator lot, one (1) instrument, one (1) calibration, three (3) testing days, four (4) blank samples with minimum of sixty (60) replicate measurements (across all blank samples, days, instrument) and four (4) samples, each containing a low level of measurand (LoD) with minimum of sixty (60) replicate measurements (across all low-level samples, days, instrument).

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Table 8. Limit of Detection Summary

Sample	Limit ofDetectionLot 1 (ng/mL)	Limit ofDetectionLot 2(ng/mL)	Limit ofDetectionFinal (ng/mL)	ClaimedLimit ofDetection(ng/mL)
LoD

8.5 Specificity and Cross-reactivity

The specificity was evaluated in accordance with CLSI EP07-ED3 Interference Testing Clinical Chemistry.

The experimental design was one (1) reagent lot, one (1) calibrator lot, one (1) instrument, one (1) sample pool for each compound tested. The samples were assayed in five (5) replicates.

Table 9. Specificity - Buprenorphine Metabolites

Compound	ConcentrationTested (ng/mL)	Mean(ng/mL)	Cutoff(ng/mL)	% Cross-reactivity
Buprenorphine	5 ng/mL	4.9	5.0	98%
Norbuprenorphine	5 ng/mL	5.3	5.0	106%
BuprenorphineGlucuronide	1,000 ng/mL	1.4	5.0	0.10%
NorbuprenorphineGlucuronide	1,000 ng/mL	1.4	5.0	0.10%

Table 10. Cross-reactivity - Structurally Related Compounds

Description	Concentration@ Testing	MeanRate(mA/min)	CutoffRate(mA/min)	Responsevs. Cutoff(Pos/Neg)	Mean(ng/mL)	%Cross-reactivity to 5ng/mL Cutoff
6-Acetylcodeine	100,000 ng/mL	131	167	Neg	-0.6	<0.1%
6-Acetylmorphine	100,000 ng/mL	137	167	Neg	0.4	<0.1%
Codeine	100,000 ng/mL	135	167	Neg	0.1	<0.1%
Dextromethorphan	100,000 ng/mL	137	167	Neg	0.3	<0.1%
Dihydrocodeine	100,000 ng/mL	136	167	Neg	0.3	<0.1%
Ethyl Morphine	100,000 ng/mL	136	167	Neg	0.3	<0.1%
Heroin	100,000 ng/mL	133	167	Neg	0.0	<0.1%
Hydrocodone	100,000 ng/mL	136	167	Neg	0.2	<0.1%

Emit® II Plus Buprenorphine Assay Traditional 510(k)

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Description	Concentration@ Testing	MeanRate(mA/min)	CutoffRate(mA/min)	Responsevs. Cutoff(Pos/Neg)	Mean(ng/mL)	%Cross-reactivity to 5ng/mL Cutoff
Hydromorphone	100,000 ng/mL	137	167	Neg	0.4	<0.1%
Levorphanol	100,000 ng/mL	141	167	Neg	1.0	<0.1%
Morphine	100,000 ng/mL	135	167	Neg	0.1	<0.1%
Morphine 3-glucuronide	100,000 ng/mL	137	167	Neg	0.4	<0.1%
Morphine 6-glucuronide	100,000 ng/mL	136	167	Neg	0.3	<0.1%
Nalorphine	100,000 ng/mL	136	167	Neg	0.3	<0.1%
Naloxone	100,000 ng/mL	138	167	Neg	0.6	<0.1%
Naltrexone	100,000 ng/mL	137	167	Neg	0.4	<0.1%
Norcodeine	100,000 ng/mL	135	167	Neg	0.1	<0.1%
Normorphine	100,000 ng/mL	136	167	Neg	0.2	<0.1%
Noroxycodone	100,000 ng/mL	135	167	Neg	0.2	<0.1%
Noroxymorphone	100,000 ng/mL	136	167	Neg	0.2	<0.1%
Oxycodone	100,000 ng/mL	136	167	Neg	0.3	<0.1%
Oxymorphone	100,000 ng/mL	137	167	Neg	0.4	<0.1%

Table 11. Cross-reactivity - Structurally Un-Related Compounds

Compound	Conc.Tested(µg/mL)	-40%ControlMean Semi-Quant(ng/mL)	-40% ControlResponse vs.Cutoff(Pos/Neg)	+40%ControlMean Semi-Quant(ng/mL)	+40% ControlResponse vs.Cutoff (Pos/Neg)
10,11-Dihydrocarbamazepine	85.0	2.8	Neg	6.9	Pos
Acetaminophen	1000.0	2.5	Neg	7.0	Pos
Acetylsalicylic Acid	1500.0	2.5	Neg	7.0	Pos
Amitriptyline	100.0	3.1	Neg	7.5	Pos
Amoxicillin	500.0	2.5	Neg	6.9	Pos
AZT (Zidovudine)	2000.0	2.5	Neg	6.8	Pos
Brompheniramine	75.0	2.7	Neg	6.9	Pos
Caffeine	1000.0	2.7	Neg	7.0	Pos
Captopril	500.0	2.6	Neg	6.9	Pos
Compound	Conc.Tested(µg/mL)	-40%ControlMean Semi-Quant(ng/mL)	-40% ControlResponse vs.Cutoff(Pos/Neg)	+40%ControlMean Semi-Quant(ng/mL)	+40% ControlResponse vs.Cutoff (Pos/Neg)
Chlordiazepoxide	100.0	2.6	Neg	7.1	Pos
Chlorpromazine	10.0	2.9	Neg	7.2	Pos
Cimetidine	1000.0	2.9	Neg	7.4	Pos
Clomipramine	2.5	2.8	Neg	7.3	Pos
Clonidine	1000.0	2.9	Neg	7.2	Pos
Cyclobenzaprine	125.0	3.1	Neg	7.6	Pos
d-Amphetamine	700.0	2.9	Neg	7.3	Pos
Desipramine	800.0	3.3	Neg	8.0	Pos
Diazepam	100.0	3.1	Neg	7.4	Pos
Digoxin	0.01	2.9	Neg	6.9	Pos
Diphenhydramine	1000.0	4.6	Neg	8.8	Pos
d-Methamphetamine	500.0	2.9	Neg	7.2	Pos
Doxepin	100.0	3.0	Neg	7.6	Pos
EDDP (2-Ethylidene-1.5dimethyl-3.3-duogenylidine)	1000.0	3.6	Neg	8.3	Pos
EMDP	100.0	2.7	Neg	7.0	Pos
Enalapril	500.0	2.7	Neg	7.3	Pos
Fluoxetine	500.0	3.0	Neg	7.8	Pos
Glutethimide	500.0	2.8	Neg	7.4	Pos
Haloperidol	100.0	2.7	Neg	7.4	Pos
Hydroxyzine (dihydrochloride)	500.0	3.3	Neg	8.0	Pos
lbuprofen	1000.0	2.9	Neg	7.4	Pos
Imipramine	200.0	3.2	Neg	7.6	Pos
Ketamine	100.0	2.6	Neg	7.0	Pos
Ketorolac Tromethamine	400.0	2.3	Neg	6.7	Pos
LAAM (L-a-AcetyImethadol)	25.0	2.7	Neg	7.4	Pos
L-Cotinine	100.0	2.6	Neg	7.0	Pos
Compound	Conc.Tested(µg/mL)	-40%ControlMean Semi-Quant(ng/mL)	-40% ControlResponse vs.Cutoff(Pos/Neg)	+40%ControlMean Semi-Quant(ng/mL)	+40% ControlResponse vs.Cutoff (Pos/Neg)
Levofloxacin	100.0	2.8	Neg	7.1	Pos
Levothyroxine (L-Thyroxine)	50.0	2.6	Neg	7.1	Pos
Lidocaine	1000.0	2.7	Neg	7.1	Pos
Lormetazepam	1.0	2.5	Neg	7.0	Pos
LSD	10.0	2.5	Neg	7.1	Pos
MDMA (Ecstasy)	1000.0	2.6	Neg	7.3	Pos
Meperidine	800.0	2.9	Neg	7.5	Pos
Methadone	500.0	3.3	Neg	7.9	Pos
Methaqualone	600.0	3.0	Neg	7.6	Pos
NAPA (N-Acetylprocainamide)	400.0	2.6	Neg	6.8	Pos
Naproxen	1000.0	2.4	Neg	6.6	Pos
Nicotinic Acid	500.0	2.5	Neg	7.2	Pos
Nifedipine	500.0	2.5	Neg	6.4	Pos
Nordiazepam	100.0	2.7	Neg	7.2	Pos
Nortriptyline	250.0	2.6	Neg	7.4	Pos
Oxazepam	300.0	2.4	Neg	6.6	Pos
Perphenazine	150.0	2.9	Neg	7.6	Pos
Phencyclidine	900.0	4.6	Neg	8.9	Pos
Phenobarbital	500.0	2.5	Neg	7.1	Pos
Phenelzine (sulfate)	100.0	2.6	Neg	6.0	Pos
Phenytoin	1000.0	2.4	Neg	6.0	Pos
Procainamide (HCI)	1000.0	2.6	Neg	7.0	Pos
Procyclidine (HCI)	800.0	3.2	Neg	8.0	Pos
Promethazine (HCI)	100.0	3.7	Neg	8.1	Pos
Propoxyphene	1000.0	3.5	Neg	8.0	Pos
Protriptyline (HCI)	200.0	3.3	Neg	7.9	Pos
Pseudoephedrine	1000.0	2.7	Neg	7.0	Pos
Compound	Conc.Tested(µg/mL)	-40%ControlMean Semi-Quant(ng/mL)	-40% ControlResponse vs.Cutoff(Pos/Neg)	+40%ControlMean Semi-Quant(ng/mL)	+40% ControlResponse vs.Cutoff (Pos/Neg)
Quinacrine (HCI)	900.0	4.8	Neg	9.0	Pos
Ranitidine	1000.0	2.6	Neg	7.1	Pos
Ritalin	1000.0	2.7	Neg	7.5	Pos
Salicylic Acid	500.0	2.5	Neg	7.1	Pos
Scopolamine	500.0	2.5	Neg	6.9	Pos
Secobarbital	1000.0	2.7	Neg	7.5	Pos
Tapentadol	100.0	2.4	Neg	7.0	Pos
THC (11-nor-A9-THC-9-COOH)	100.0	2.4	Neg	6.7	Pos
Thioridazine	100.0	4.1	Neg	8.6	Pos
Tramadol	1000.0	3.0	Neg	7.8	Pos
Trazodone	5.0	2.4	Neg	6.8	Pos
Trimethoprim	1000.0	2.5	Neg	7.1	Pos
Triprolidine (zymine)	50.0	2.6	Neg	7.2	Pos
Tyramine	100.0	2.5	Neg	6.9	Pos
Verapamil	500.0	2.8	Neg	7.6	Pos
Zolpidem	100.0	2.7	Neg	7.1	Pos

Emit® II Plus Buprenorphine Assay Traditional 510(k)

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Emit® II Plus Buprenorphine Assay Traditional 510(k)

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Emit® II Plus Buprenorphine Assay Traditional 510(k)

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8.6 Interference

Interference was evaluated in accordance with CLSI EP07-ED3 Interference Testing Clinical Chemistry.

Urine testing samples were prepared by spiking exogenous materials (metabolites and structurally related compounds) into urine samples at ± 40% positive and negative control levels (3 ng/mL and 7 ng/mL respectively).

The experimental design was one (1) reagent lot, one (1) calibrator lot, one (1) instrument, one (1) sample pool for each compound tested. The samples were assayed in five (5) replicates.

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InterferentSample	Interferenceconcentration	-40%ControlResponsevs. QualCutoff(Pos/Neg)	-40%ControlSampleMean(ng/mL)	+40%ControlResponsevs. QualCutoff(Pos/Neg)	+40%ControlSampleMean(ng/mL)
Acetone	1.0 g/dL	Neg	2.6	Pos	6.3
Ascorbic Acid	1.5 g/dL	Neg	2.9	Pos	6.3
Bilirubin(Conjugated)	2.0 mg/dL	Neg	2.2	Pos	6.2
Bilirubin(Unconjugated)	2.0 mg/dL	Neg	2.4	Pos	5.9
Creatinine	0.5 g/dL	Neg	2.7	Pos	6.3
Ethanol	1.0 g/dL	Neg	2.5	Pos	6.4
IgG	0.5 g/dL	Neg	2.5	Pos	7.1
Glucose	2.0 g/dL	Neg	2.5	Pos	6.1
Hemoglobin	115 mg/dL	Neg	3.0	Pos	6.7
Human SerumAlbumin	0.5 g/dL	Neg	2.9	Pos	6.7
Oxalic Acid	0.1 g/dL	Neg	2.5	Pos	6.5
Riboflavin	7.5 mg/dL	Neg	2.5	Pos	6.4
Sodium Chloride	6.0 g/dL	Neg	2.5	Pos	6.6
Urea	6.0 g/dL	Neg	2.4	Pos	6.2
Sodium Azide	1% w/v	Neg	2.5	Pos	6.4
Sodium Fluoride	1% w/v	Neg	2.5	Pos	6.1
Galactose	1.0 g/dL	Neg	2.5	Pos	5.8
InterferentSample	-40% ControlResponse vs.Qual Cutoff(Pos/Neg)	-40%ControlMean(ng/mL)	+40% ControlResponse vs.Qual Cutoff(Pos/Neg)	+40%ControlMean(ng/mL)
pH 3	Neg	2.9	Pos	7.2
pH 4	Neg	2.9	Pos	7.5
pH 5	Neg	3.0	Pos	7.3
pH 6	Neg	3.0	Pos	7.3
pH 7	Neg	2.6	Pos	7.0
pH 8	Neg	2.4	Pos	6.9
pH 9	Neg	2.6	Pos	6.2
pH 10	Neg	2.6	Pos	6.0
pH 11	Neg	2.5	Pos	6.2
sG 1.002	Neg	2.7	Pos	6.4
sG 1.005	Neg	2.9	Pos	6.8
sG 1.010	Neg	2.9	Pos	7.0
sG 1.015	Neg	2.9	Pos	7.2
sG 1.020	Neg	2.9	Pos	7.2
sG 1.025	Neg	3.0	Pos	7.2
sG 1.030	Neg	2.6	Pos	7.0
sG 1.035	Neg	2.5	Pos	6.9

Table 12. Interference – Endogenous and Exogenous Substances

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Table 13. Interference – pH and Specific Gravity

9. Conclusion

Based on a comparison of the technological characteristic similarities and differences, the Emit® II Plus Buprenorphine Assay (K150606) and the Emit® II Plus Buprenorphine Assay have equivalent intended use and technology attributes. Performance studies were completed to demonstrate the performance of the proposed device to the predicate device were substantially equivalent. Through the accuracy comparison of both methods to the reference LC/MS/MS as well as performance studies of precision, recovery, and specificity, the substantial equivalence is supported.

Regulation Number and Section

§ 862.3650 Opiate test system.

(a)
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.(b)
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).