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 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. 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.

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 Control Negative and Emit® II Plus Specialty Drug Control Positive

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

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 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 liguid. 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 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.

Emit® II Plus Specialty Drug Calibrators / Controls are in-vitro diagnostic products 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. The matrix is pooled, drug-free, human urine based product containing buprenorphine, preservatives and surfactants. Each level of calibrator is packaged and sold separately, 1 plastic bottle per box, 10 mL in a 15 mL bottle. Values are nominal and are verified with urine based buprenorphine anchor pool and adjusted if needed. The anchor pool levels are verified by LC/MS/MS and are within 10% of nominal drug concentration for levels 2.5 and 5.0 ng/mL and within 5 % of nominal concentrations for levels 15 and 25 ng/mL.

Emit® II Plus Specialty Drug Control Negative and Emit® II Plus Specialty Drug Control Positive are in-vitro diagnostic products are for use with the Emit® II Plus Buprenorphine assay. The matrix is pooled, drug-free, human urine based product containing buprenorphine, preservatives and surfactants. The Control Negative and Control Positive are packaged separately in 15 mL plastic vials with a 10 mL fill per vial. Values are nominal and are verified with urine based buprenorphine anchor pool and adjusted if needed. Anchor pool levels are verified by LC/MS/MS.

AI/ML Overview

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Device: Emit® II Plus Buprenorphine Assay, Emit® II Plus Specialty Drug Calibrator/Control Level 1-4, Emit® II Plus Specialty Drug Control Negative/Positive.

Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numbered or bulleted points in the provided document. However, based on the performance data presented, we can infer the criteria that the device aimed to meet for substantial equivalence. The document primarily focuses on demonstrating performance against expected standards for an in vitro diagnostic device for drug screening, particularly a qualitative and semi-quantitative assay.

Here's a table summarizing the inferred acceptance criteria and the device's performance:

Acceptance Criteria Category/Inferred Criteria	Reported Device Performance
Precision (Qualitative Analysis) - Agreement near cutoff - Consistent classification (Negative/Positive) for concentrations significantly below/above cutoff. - Acceptable level of concordant/discordant results near the cutoff for both qualitative and semi-quantitative modes.	Precision: Qualitative Analysis (5 ng/mL cutoff) - 0, 2.5, 3, 3.75 ng/mL (below cutoff): 80 Negative out of 80 results (100% agreement). - 5 ng/mL (cutoff): 25 Negative / 55 Positive (68.75% positive, 31.25% negative). This indicates some variability at the exact cutoff, which is typical for immunoassays. - 6.25, 7, 7.5, 10 ng/mL (above cutoff): 80 Positive out of 80 results (100% agreement). - Additional Precision Study: - 1.25 ng/mL (-75% cutoff): 80 Negative out of 80 results (100% agreement). - 8.75 ng/mL (+75% cutoff): 80 Positive out of 80 results (100% agreement). Overall, good precision away from the cutoff, expected variability at the cutoff.
Precision (Semi-quantitative Analysis) - Agreement near cutoff - Consistent classification (Negative/Positive) and semi-quantitative results for concentrations significantly below/above cutoff.	Precision: Semi-quantitative Analysis (5 ng/mL cutoff) - 0, 2.5, 3, 3.75 ng/mL (below cutoff): 80 Negative out of 80 results (100% agreement). - 5 ng/mL (cutoff): 25 Negative / 55 Positive (68.75% positive, 31.25% negative). - 6.25, 7, 7.5, 10 ng/mL (above cutoff): 80 Positive out of 80 results (100% agreement). - Additional Precision Study: - 1.25 ng/mL (-75% cutoff): 80 Negative out of 80 results (100% agreement). - 8.75 ng/mL (+75% cutoff): 80 Positive out of 80 results (100% agreement). Results mirror qualitative analysis, demonstrating consistent semi-quantitative performance.
Specificity and Cross-reactivity - Buprenorphine Metabolites - Appropriate cross-reactivity with buprenorphine and its primary active metabolite (norbuprenorphine). - Low to no cross-reactivity with inactive glucuronide metabolites.	Buprenorphine Metabolite Recovery - Buprenorphine (5 ng/mL): 103.2% recovery (5.2 ng/mL). - Norbuprenorphine (5 ng/mL): 92.6% recovery (4.6 ng/mL). - Buprenorphine Glucuronide (1000 ng/mL): 0.1% cross-reactivity (0.9 ng/mL). - Norbuprenorphine Glucuronide (1000 ng/mL): 0.1% cross-reactivity (1.2 ng/mL). Demonstrates good detection of buprenorphine and norbuprenorphine, minimal interference from inactive glucuronide metabolites.
Specificity and Cross-reactivity - Structurally Related Compounds - No significant false positives from a panel of common opioids and other structurally related compounds at high concentrations.	Cross-reactivity with Structurally Related Compounds - Over 20 common opioids and related compounds (e.g., 6-acetylcodeine, codeine, heroin, morphine, oxycodone) were tested at 100,000 ng/mL. - All tested compounds showed "Negative" qualitative results and "<0.01%" cross-reactivity (semi-quantitative). Excellent specificity, not cross-reacting with a wide range of other opioids at very high concentrations, which is critical for drug screening assays.
Interference - Structurally Unrelated Compounds - No false positive or false negative results from a panel of common medications and other substances expected in urine at clinically relevant concentrations.	Interference of Structurally Unrelated Compounds - Over 50 structurally unrelated compounds (e.g., acetaminophen, amoxicillin, caffeine, ibuprofen, fluoxetine, methadone, naproxen, phencyclidine, THC) were tested. - Each interferent was spiked into urine pools at -40% cutoff (3 ng/mL buprenorphine) and +40% cutoff (7 ng/mL buprenorphine). - At the stated concentration for each interferent, all "-40% Cutoff" samples remained Negative and all "+40% Cutoff" samples remained Positive, for both qualitative and semi-quantitative results. Demonstrates good resistance to interference from a broad range of common drugs and substances.
Interference - Endogenous Substances - No false positive or false negative results due to endogenous substances, pH, or specific gravity variations.	Endogenous Substances Interference, pH, and Specific Gravity - 15 endogenous substances (e.g., acetone, ascorbic acid, bilirubin, creatinine, ethanol, glucose, hemoglobin, urea) were tested at high concentrations. - pH range (pH 3 to pH 11) and Specific Gravity range (1.002 to 1.035) were tested. - For all endogenous substances, pH levels, and specific gravity levels, the -40% cutoff samples remained Negative, and the +40% cutoff samples remained Positive, for both qualitative and semi-quantitative results. Indicates robust performance across a range of physiological conditions and common urine constituents.
Recovery/Linearity - Accurate semi-quantitative recovery of buprenorphine across a range of concentrations.	Recovery/Linearity - Tested nine concentrations of buprenorphine from 2 ng/mL to 25 ng/mL. - % Recovery ranged from 92.5% to 105.0%. Demonstrates good linearity and accurate recovery of buprenorphine concentrations over the tested range.
Method Comparison (Qualitative and Semi-quantitative) - Agreement with Reference Method - High agreement with a more specific, confirmatory method (LC/MS/MS). - Acceptable number of discordant results, with plausible explanations for any discrepancies.	Method Comparison (Emit® II Plus Buprenorphine Assay vs. LC/MS/MS) - Total Samples: 127 unaltered human urine samples. - Qualitative Agreement: 90% positive agreement, 98% negative agreement. - Overall Agreement (from 2x2 table): (65 + 54) / 127 = 119 / 127 = 93.7%. - Discordant Results (8 samples): - 7 samples were Emit® Positive but LC/MS/MS Negative (concentration between 3.86-4.97 ng/mL, below 5 ng/mL cutoff for LC/MS/MS buprenorphine/norbuprenorphine sum). These are typically considered "near cutoff" false positives for a screening assay. - 1 sample was Emit® Negative but LC/MS/MS Positive (buprenorphine at 5.12 ng/mL). This is a single false negative near the cutoff. High overall agreement with LC/MS/MS, with expected discordance at concentrations close to the cutoff, demonstrating performance comparable to drug screening immunoassays.

Study Details:

Sample Size used for the test set and data provenance:
- Precision/Cutoff Characterization: For the main precision study, 8 urine pools were tested (0, 2.5, 3, 3.75, 5, 6.25, 7, 7.5, 10 ng/mL). Each pool was analyzed in duplicate twice a day for 20 days, resulting in 80 replicates per concentration level (total 720 replicates) for the main study. An additional precision study used 2 urine pools (1.25 and 8.75 ng/mL), with 80 replicates each (total 160 replicates). The urine was "drug-free human urine" spiked with buprenorphine.
- Specificity and Cross-reactivity (Metabolites): Each metabolite was tested at n=5 replicates.
- Specificity and Cross-reactivity (Structurally Related Compounds): Each compound was tested at n=5 replicates.
- Interference (Structurally Unrelated Compounds): Each interferent was tested at n=5 replicates (at both -40% and +40% cutoff levels).
- Interference (Endogenous Substances): Each endogenous substance, pH level, and specific gravity level was tested (N=not explicitly stated, but typically n=5 replicates as above).
- Recovery/Linearity: Nine concentrations were analyzed in replicates of N=5.
- Method Comparison: 127 unaltered human urine samples were used.
- Data Provenance: The document states studies were conducted at "Siemens Healthcare Diagnostics Inc." and used "human urine" (drug-free or unaltered). No specific country of origin is mentioned. It is an internal, retrospective study using banked samples or samples collected for the purpose of the study.
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), which is a highly specific and sensitive analytical method considered a "confirmatory method." This is a laboratory-based instrumental method, not established by human experts in the traditional sense of medical image interpretation or clinical diagnosis. The "experts" would be the laboratory personnel operating and interpreting the LC/MS/MS results, qualified in analytical chemistry and toxicology testing. Their number and specific qualifications are not specified in this document.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- For the method comparison, the ground truth was established by LC/MS/MS as a single, definitive reference method. There was no multi-expert adjudication mentioned as would be common in diagnostic imaging studies. The LC/MS/MS result serves as the "gold standard."
If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay (a chemical test) and operates independently of human "readers" or "AI assistance" in the way that imaging devices or AI-driven diagnostic software would. The output is a numerical value or a qualitative (positive/negative) result generated by an automated analyzer.
If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- Yes, the provided performance data represents standalone performance. The Emit® II Plus Buprenorphine Assay is an automated immunoassay designed for use on chemistry analyzers. All precision, specificity, interference, linearity, and method comparison data reflect the assay's performance without "human-in-the-loop" interpretation beyond running the assay and recording the results. The ultimate interpretation and clinical judgment for drug-of-abuse test results might involve a human, but the analytical performance presented is the measurement device's standalone capability.
The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- The ground truth for the performance studies, particularly the crucial method comparison, was established by LC/MS/MS (Liquid Chromatography/Mass Spectrometry/Mass Spectrometry). This is an analytical reference method considered the gold standard for confirming drug presence and concentration in toxicology.
The sample size for the training set:
- This document describes performance characteristics of a diagnostics assay for regulatory submission. It does not refer to a "training set" in the context of machine learning. The "training" of such a device primarily involves the development and optimization of the reagent formulation and assay parameters during the product development phase, which isn't typically quantified by a distinct "training set sample size" like in AI/ML development. The precision studies use spiked urine, which could be considered part of the characterization but not a "training set" in the modern AI sense.
How the ground truth for the training set was established:
- Given that this is not an AI/ML device but a chemical immunoassay, the concept of a "ground truth for a training set" as typically understood in AI/ML performance studies does not directly apply. The calibration and control materials are manufactured to known (targeted) concentrations, and their values are "verified with urine based buprenorphine anchor pool and adjusted if needed," with anchor pool levels "verified by LC/MS/MS." This implies that the 'true' concentrations for calibrators and controls used to define the assay's performance characteristics are established via LC/MS/MS.

Summary

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Image /page/0/Picture/1 description: The image is a seal for the Department of Health & Human Services - USA. The seal is circular, with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. In the center of the seal is a stylized image of three human profiles facing to the right. The profiles are stacked on top of each other, creating a sense of depth and unity.

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

October 23, 2015

SIEMENS HEALTHCARE DIAGNOSTICS, INC. FRANCES DILLON SR. MANAGER, REGULATORY AFFAIRS P.O. BOX 6101, M/S 514 NEWARK DE 19714-6101

Re: K150606

Trade/Device Name: Emit II Plus Buprenorphine Assay,

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. Emit II Plus Specialty Drug Control Negative, Emit II Plus Specialty Drug Control Positive

Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate test system Regulatory Class: II Product Code: DJG, DLJ, LAS Dated: September 4, 2015 Received: September 8, 2015

Dear Ms. Dillon:

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

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CFR Part 807): labeling (21 CFR Parts 801 and 809); medical device reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 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 (800) 638-2041 or (301) 796-7100 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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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

510(k) Number (if known) K150606

Device Name

Emit® II Plus Buprenorphine Assay, 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, Emit® II Plus Specialty Drug Control Negative, Emit® II Plus Specialty Drug Control Positive,

Indications for Use (Describe) Emit® II Plus Buprenorphine Assay

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

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

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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510(K) Summary

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

The assigned 510(k) number is: K150606

1. Submitter

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

Tel: 302-631-6951 FAX: 3023-631-6299

Contact Person: Frances Dillon Date of Preparation: October 20, 2015

2. Device Information

Trade Name:	Emit® II Plus Buprenorphine Assay
Common Name:	Buprenorphine Assay
Classification Name:	Opiates test system - 21CFR 862.3650
Regulatory Class:	II
Product Code:	DJG - Enzyme Immunoassay, Opiates
Panel:	Clinical Toxicology (91)
Trade Name:	Emit® II Plus Specialty Drug Calibrator/Control Level 1Emit® II Plus Specialty Drug Calibrator/Control Level 2Emit® II Plus Specialty Drug Calibrator/Control Level 3Emit® II Plus Specialty Drug Calibrator/Control Level 4
Common Name:	Buprenorphine Calibrator/Control
Classification Name:	Clinical Toxicology Calibrator - 21CFR 862.3200Clinical Toxicology Control Material - 21CFR 862.3280
Regulatory Class:	II (Calibrator)I (Control)
Product Code:	DLJ - Calibrators, Drug SpecificLAS - Drug Specific Control Materials
Panel:	Clinical Toxicology (91)
Trade Name:	Emit® II Plus Specialty Drug Control NegativeEmit® II Plus Specialty Drug Control Positive
Common Name:	Buprenorphine Negative Control and BuprenorphinePositive Control
Classification Name:	Clinical Toxicology Control material - 21CFR 862.3280
Regulatory Class:	I
Product Code:	LAS - Drug Specific Control Materials
Panel:	Clinical Toxicology (91)

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3. Predicate Device

Assay:	Microgenics CEDIA® Buprenorphine Assay, K040316.
Calibrator:	Microgenics CEDIA® Buprenorphine Calibrators, K040316.
Control:	Microgenics CEDIA® Buprenorphine Controls, K040316.

4. Device Description

Assav

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 / Controls

Emit® II Plus Specialty Drug Calibrator/Control levels are as follows:

Specialty Drug Calibrator/Control	Targeted Buprenorphine Concentration(ng/mL
Level 1	2.5
Level 2	5
Level 3	15
Level 4	25

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The Emit® Calibrator/Control Level 0, which contains no drug and was cleared under K993755 is used with the Emit® II Plus Buprenorphine Assay. There are no changes to the Calibrator Level 0 product. Controls

Emit® II Plus Specialty Drug Control Negative and Control Positive levels are as follows:

Specialty Drug Control	Targeted Buprenorphine Concentration(ng/mL)
Negative	3
Positive	7

5. Indications for Use

Emit® II Plus Buprenorphine Assay

Emit® II Plus Buprenorphine Assay is a homogeneous enzyme immunoassay with a 5 nq/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 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, Level 2, Level 3, and Level 4

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

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

Attributes	Predicate DeviceCEDIA® Buprenorphine Assay(K040316)	Proposed DeviceEmit® II PlusBuprenorphine Assay
Similarities
Intended Use	A homogeneous enzymeimmunoassay for qualitative orsemi-quantitative determination ofthe presence of buprenorphine inhuman urine at a cutoffconcentration of 5 ng/mL.Preliminary analytical test result.	Same
Analyte	Buprenorphine	Same
Antibody	Mouse monoclonal antibody tobuprenorphine	Same
Test System	Homogeneous enzymeimmunoassay	Same
Detection	Absorbance change measuredspectrophotometrically	Same
Sample type	Human urine	Same
Cutoff Level	5 ng/mL	Same
Instrument	Automated clinical analyzerscapable of maintaining a constanttemperature, pipetting, mixingreagents, measuring enzymaticrates, and timing the reaction.	Same
Calibrator levels	0 ng/mL + four (4) levels	Same
Control Levels	High Control 7 ng/mLLow Control 3 ng/mL	Same
Differences
Assaymethodology	Uses CEDIA® technology	Uses EMIT® technology
Detection	Absorbance change measuredspectrophotometrically at 660 nm.	Absorbance changemeasuredspectrophotometrically at340 nm.
ReferenceMethodology	GC/MS	LC/MS
Reagents Form	R1 and R2: Lyophilized(Reconstitution Required)	R1: Liquid - Ready to useR2: Liquid - Ready to use
Calibrator levels	0, 5, 20, 50, and 75 ng/mL	0, 2.5, 5, 15, and 25 ng/mL

6. Comparison of Technological Characteristics with the Predicate Device

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Comparison of Calibrator/Control Similarities and Differences

Attributes	Predicate DeviceCEDIA® BuprenorphineCalibrator (K040316)	Proposed DeviceEmit® II Plus SpecialtyDrug Calibrator / Control
Similarities
Intended Use	The CEDIA® Buprenorphinecalibrators are used tocalibrate the CEDIA®Buprenorphine Assay inhuman urine.	Same
Matrix	Human urine	Same
Analyte	Buprenorphine	Same
Preparation	Liquid - Ready to use	Same
Storage	2 – 8 °C	Same
Differences
TargetConcentrations forBuprenorphine	0, 5, 20, 50, and 75 ng/mL	2.5, 5, 15, and 25 ng/mL(0 ng/mL calibrator is Emit®Calibrator/Control Level 0)

Comparison of Control Similarities

Attributes	Predicate DeviceCEDIA® BuprenorphineNegative Control andPositive Control (K040316)	Proposed DeviceEmit® II Plus SpecialtyDrug Control Negativeand Control Positive
Similarities
Intended Use	The CEDIA® Buprenorphinecontrols are used to qualifythe CEDIA® BuprenorphineAssay in human urine.	Same
Matrix	Human urine	Same
Analyte	Buprenorphine	Same
TargetConcentrations forBuprenorphine	High Control 7 ng/mLLow Control 3 ng/mL	Same
Preparation	Liquid, ready to use	Same
Storage	2 – 8ºC	Same

7. Performance Data

Performance of the Emit® II Plus Buprenorphine Assay was evaluated at Siemens Healthcare Diagnostics Inc. on a Viva-E® Analyzer.

a. Precision / Cutoff Characterization

Studies were conducted using urine pools prepared by spiking Buprenorphine into drug-free human urine at 8 concentrations (levels). The concentrations tested represent the following levels relative to the 5 ng/mL cutoff: 100, -50%,

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-40%, and -25% below the cutoff, at the cutoff, and +25%, +40%, +50%, and +100% of the cutoff. The drug-free human urine pool was also tested as the 0 ng/mL buprenorphine level. The studies were performed on Viva-E® analyzer. For each level, samples were analyzed in duplicate twice a day, for 20 days (N=80).

Urine Pool(ng/mL)	% ofCutoff	# ofResults	RepeatabilityResults	Within-LaboratoryResults
O	-100%	80	80 Negative	80 Negative
2.5	-50%	80	80 Negative	80 Negative
3	-40%	80	80 Negative	80 Negative
3.75	-25%	80	80 Negative	80 Negative
5	cutoff	80	25 Negative/55 Positive	25 Negative/55 Positive
6.25	+25%	80	80 Positive	80 Positive
7	+40%	80	80 Positive	80 Positive
7.5	+50%	80	80 Positive	80 Positive
10	+100%	80	80 Positive	80 Positive

Precision: Qualitative Analysis

Precision: Semi-quantitative Analysis

Urine Pool(ng/mL)	% ofCutoff	# ofResults	RepeatabilitvResults	Within-LaboratoryResults
0	-100%	80	80 Negative	80 Negative
2.5	-50%	80	80 Negative	80 Negative
3	-40%	80	80 Negative	80 Negative
3.75	-25%	80	80 Negative	80 Negative
5	cutoff	80	25 Negative/55 Positive	25 Negative/55 Positive
6.25	+25%	80	80 Positive	80 Positive
7	+40%	80	80 Positive	80 Positive
7.5	+50%	80	80 Positive	80 Positive
10	+100%	80	80 Positive	80 Positive

An additional precision study was performed using urine pools prepared by spiking Buprenorphine into drug-free human urine at one concentration level

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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 over one day.

Urine Pool(ng/mL)	% ofCutoff	# ofResults	RepeatabilityResults	Within-LaboratoryResults
1.25	-75%	80	80 Negative	80 Negative
8.75	+75%	80	80 Positive	80 Positive

Precision: Qualitative Analysis

Precision: Semi-Quantitative Analysis

Urine Pool(ng/mL)	% ofCutoff	# ofResults	RepeatabilityResults	Within-LaboratoryResults
1.25	-75%	80	80 Negative	80 Negative
8.75	+75%	80	80 Positive	80 Positive

b. Specificity and Cross-reactivity

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.

Buprenorphine and Buprenorphine Metabolite Recovery

Compound	ConcentrationTested(ng/mL)	Semi-quantitativeResults
		Recovery(ng/mL)	% Cross-reactivity
Buprenorphine	5	5.2	103.2
Norbuprenorphine	5	4.6	92.6
BuprenorphineGlucuronide	1000	0.9	0.1
NorbuprenorphineGlucuronide	1000	1.2	0.1

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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.

For qualitative analysis, cross-reactivity is reported as the level of crossreactant that produces a rate response ≥ the cutoff. For semi-quantitative analysis the percent cross-reactivity was calculated.

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

Cross-reactivity with the Structurally Related Compound

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c. Interference

Structurally Unrelated Compounds - Interference from the structurally unrelated compounds was evaluated by spiking each compound into a 3 ng/mL and 7 ng/mL spiked urine pool. A control (blank) was also prepared without the interferent compound. Samples were evaluated on the Viva-E® analyzer. The blank sample was run, followed by the sample containing the interfering compound. All samples were tested in replicates of N=5. The mean rate and concentration were calculated for qualitative and semiquantitative analysis, respectively. The sample containing the drug was compared to the control, which contained only buprenorphine (3 or 7 ng/mL) to determine if there was a false response relative to the assay cutoff (5 ng/mL). At the stated concentration, the samples did not give a false response relative to the 5 ng/mL cutoff.

		- 40% Cutoff (3 ng/mL)		+40% Cutoff (7 ng/mL)
Interference(StructurallyUnrelatedCompounds)	Conc.Tested(ug/mL)	QualitativeResult	Semi-quantitativeResult	QualitativeResult	Semi-quantitativeResult
10. 11-dihydrocarbamazepine	85	Negative	Negative	Positive	Positive
Acetaminophen	1000	Negative	Negative	Positive	Positive
Acetylsalicylic Acid	1500	Negative	Negative	Positive	Positive
Amitriptyline	100	Negative	Negative	Positive	Positive
Amoxicillin	500	Negative	Negative	Positive	Positive
ZT (Zidovudine)	2000	Negative	Negative	Positive	Positive
Benzoylecgonine	1000	Negative	Negative	Positive	Positive
Brompheniramine	75	Negative	Negative	Positive	Positive
Caffeine	1000	Negative	Negative	Positive	Positive
Captopril	500	Negative	Negative	Positive	Positive
Chlordiazepoxide	100	Negative	Negative	Positive	Positive
Chlorpromazine	10	Negative	Negative	Positive	Positive
Cimetidine	1000	Negative	Negative	Positive	Positive
Clomipramine	2.5	Negative	Negative	Positive	Positive
Clonidine	1000	Negative	Negative	Positive	Positive
Cyclobenzaprine	125	Negative	Negative	Positive	Positive
d-amphetamine	700	Negative	Negative	Positive	Positive
Desipramine	800	Negative	Negative	Positive	Positive
Diazepam	100	Negative	Negative	Positive	Positive
Digoxin	0.01	Negative	Negative	Positive	Positive
Diphenhydramine	1000	Negative	Negative	Positive	Positive
d-methamphetamine	500	Negative	Negative	Positive	Positive
Doxepine	100	Negative	Negative	Positive	Positive
EDDP	1000	Negative	Negative	Positive	Positive
EMDP	100	Negative	Negative	Positive	Positive
Enalapril	500	Negative	Negative	Positive	Positive
Fluoxetine	500	Negative	Negative	Positive	Positive
Glutethimide	500	Negative	Negative	Positive	Positive
Haloperidol	100	Negative	Negative	Positive	Positive
Hydroxyzine	500	Negative	Negative	Positive	Positive
Ibuprophen	1000	Negative	Negative	Positive	Positive
Imipramine	200	Negative	Negative	Positive	Positive
Ketamine	100	Negative	Negative	Positive	Positive
KetorolacTromethamine	400	Negative	Negative	Positive	Positive
LAAM (L-a-acetylmethadol)	25	Negative	Negative	Positive	Positive
L-Cotinine	100	Negative	Negative	Positive	Positive
Levofloxacin	100	Negative	Negative	Positive	Positive
Levothyroxine (L-Thyroxine)	50	Negative	Negative	Positive	Positive
Lidocaine	1000	Negative	Negative	Positive	Positive
Lormetazepam	1	Negative	Negative	Positive	Positive
LSD	10	Negative	Negative	Positive	Positive
MDMA (Ecstasy)	1000	Negative	Negative	Positive	Positive
Meperidine	800	Negative	Negative	Positive	Positive
Methadone	500	Negative	Negative	Positive	Positive
Methaqualone	600	Negative	Negative	Positive	Positive
NAPA	400	Negative	Negative	Positive	Positive
Naproxen	1000	Negative	Negative	Positive	Positive
Nicotinic Acid	500	Negative	Negative	Positive	Positive
Nifedipine	500	Negative	Negative	Positive	Positive
Nordiazepam	100	Negative	Negative	Positive	Positive
Nortryptiline	250	Negative	Negative	Positive	Positive
Oxazepam	300	Negative	Negative	Positive	Positive
Perphenazine	150	Negative	Negative	Positive	Positive
Phencyclidine	900	Negative	Negative	Positive	Positive
Phenobarbital	500	Negative	Negative	Positive	Positive
Phenelzine	100	Negative	Negative	Positive	Positive
Phenytoin	1000	Negative	Negative	Positive	Positive
Procainamide	1000	Negative	Negative	Positive	Positive
Procyclidine	800	Negative	Negative	Positive	Positive
Promethazine	100	Negative	Negative	Positive	Positive
Propoxyphene	1000	Negative	Negative	Positive	Positive
Protriptyline	200	Negative	Negative	Positive	Positive
Pseudoephedrine	1000	Negative	Negative	Positive	Positive
Quinacrine	900	Negative	Negative	Positive	Positive
Ranitidine	1000	Negative	Negative	Positive	Positive
Ritalin	1000	Negative	Negative	Positive	Positive
Salicylic Acid	500	Negative	Negative	Positive	Positive
Scopolamine	500	Negative	Negative	Positive	Positive
Secobarbital	1000	Negative	Negative	Positive	Positive
Tapentadol	100	Negative	Negative	Positive	Positive
THC	100	Negative	Negative	Positive	Positive
Thioridazine	100	Negative	Negative	Positive	Positive
Tramadol	1000	Negative	Negative	Positive	Positive
Trazodone	5	Negative	Negative	Positive	Positive
Trimethoprim	1000	Negative	Negative	Positive	Positive
Triprolidine (zymine)	50	Negative	Negative	Positive	Positive
Tyramine	100	Negative	Negative	Positive	Positive
Verapamil	500	Negative	Negative	Positive	Positive
Zolpidem	100	Negative	Negative	Positive	Positive

Interference of Structurally Unrelated Compounds

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Endogenous Substances Interference - Each compound was spiked into a -40% cutoff and a +40% cutoff which was prepared by spiking buprenorphine to aliquots of drug-free human urine. The results show that the endogenous substances, pH and sG caused no interference relative to the 5 ng/mL cutoff. Qualitative and semi-quantitative results are provided.

		-40% Cutoff (3 ng/mL)		+40% Cutoff (7 ng/mL)
Interferences(EndogenousSubstances)	Conc.Tested	QualitativeResult	Semi-QuantitativeResult	QualitativeResult	Semi-QuantitativeResult
Acetone	1.0 g/dL	Negative	Negative	Positive	Positive
Ascorbic Acid	1.5 g/dL	Negative	Negative	Positive	Positive
Conjugated Bilirubin	2.0 mg/dL	Negative	Negative	Positive	Positive
Unconjugated Bilirubin	2.0 mg/dL	Negative	Negative	Positive	Positive
Creatinine	0.5 g/dL	Negative	Negative	Positive	Positive
Ethanol	1.0 g/dL	Negative	Negative	Positive	Positive
Immuno GammaGlobulin (IgG)	0.5 g/dL	Negative	Negative	Positive	Positive
Glucose	2.0 g/dL	Negative	Negative	Positive	Positive
Galactose	1.0 g/dL	Negative	Negative	Positive	Positive
Hemoglobin	115 mg/dL	Negative	Negative	Positive	Positive
Human Serum Albumin	0.5 g/dL	Negative	Negative	Positive	Positive
Oxalic Acid	0.1 g/dL	Negative	Negative	Positive	Positive
Riboflavin	7.5 mg/dL	Negative	Negative	Positive	Positive
Sodium Chloride	6.0 g/dL	Negative	Negative	Positive	Positive
Urea	6.0 g/dL	Negative	Negative	Positive	Positive
Sodium Azide	1% w/v	Negative	Negative	Positive	Positive
Sodium Fluoride	1% w/v	Negative	Negative	Positive	Positive

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	PotentialInterference(pH)	-40% Cutoff (3 ng/mL)QualitativeResult	Semi-QuantitativeResult	+40% Cutoff (7 ng/mL)QualitativeResult	Semi-QuantitativeResult
	pH 3	Negative	Negative	Positive	Positive
	pH 4	Negative	Negative	Positive	Positive
	pH 5	Negative	Negative	Positive	Positive
	pH 6	Negative	Negative	Positive	Positive
	pH 7	Negative	Negative	Positive	Positive
	pH 8	Negative	Negative	Positive	Positive
	pH 9	Negative	Negative	Positive	Positive
	pH 11	Negative	Negative	Positive	Positive
PotentialInterference(Specific Gravity)	-40% Cutoff (3 ng/mL)Qualitative Result	-40% Cutoff (3 ng/mL)Semi-Quantitative Result	+40% Cutoff (7 ng/mL)Qualitative Result	+40% Cutoff (7 ng/mL)Semi-Quantitative Result
sG 1.002	Negative	Negative	Positive	Positive
sG 1.005	Negative	Negative	Positive	Positive
sG 1.010	Negative	Negative	Positive	Positive
sG 1.015	Negative	Negative	Positive	Positive
sG 1.020	Negative	Negative	Positive	Positive
sG 1.025	Negative	Negative	Positive	Positive
sG 1.030	Negative	Negative	Positive	Positive
sG 1.035	Negative	Negative	Positive	Positive

d. Recovery/Linearity

Drug free urine pools were spiked with nine concentrations of buprenorphine at levels 2-25 ng/mL and analyzed semi-quantitatively in replicates of N= 5 on a Viva-E® analyzer. The mean observed Buprenorphine concentration was compared to the expected Buprenorphine concentration and percent recovery calculated.

ExpectedBuprenorphineConcentration(ng/mL)	Mean BuprenorphineConcentration by Emit®Il Plus BuprenorphineAssay (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

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e. Method Comparison

Split sample method comparison was conducted with one-hundred twenty seven (127) unaltered human urine samples, which were analyzed by the Emit® II Plus Buprenorphine Assay on a Viva-E® Analyzer vs. LC/MS/MS. The results are presented below:

LC/MS/MS					%Agreement
Negative(<2.5 ng/mL)	Negative Within 50%below thecutoff (2.5-4.9 ng/mL)	Positive Within 50%above thecutoff (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%
Emit® Negative	45	9	1	0	98%

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

Comparison Table for Qualitative and Semi-quantitative Assay Performance

		LC/MS/MS
		+	-
Emit® II PlusBuprenorphine	+	65	7
	-	1	54

Discordant Result Summary

SampleID	Emit® II PlusBuprenorphine(ng/mL)	LC/MS/MS			Emit+/-	LC/MS/MS+/-
		Bup(ng/mL)	NorBup(ng/mL)	Bup+NorBup(ng/mL)
190	5.6	0	3.92	3.92	+	-
193	6.1	0	4.97	4.97	+	-
195	5.4	0	4.06	4.06	+	-
226	5.8	0	4.21	4.21	+	-
250	5.1	0	4.13	4.13	+	-
77	5.5	0	4.60	4.60	+	-
316	5.7	0	3.86	3.86	+	-
338	4.3	5.12	0	5.12	-	+

Bup = Buprenorphine; NorBup = Norbuprenorphine

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Calibrator/Control and Cutoff Control Traceability f.

The Emit® II Plus Specialty Drug Calibrator/Control and Emit® II Plus Specialty Drug Control Neqative and Control Positive are traceable to Cerilliant Buprenorphine Cat. No. B-902. When stored refrigerated at 2-8°C the calibrators/controls are stable opened or unopened until the expiration date printed on the vial label.

8. Conclusion

The information provided in this premarket notification demonstrates the Emit® II Plus Buprenorphine Assay, Emit® II Plus Specialty Drug Calibrator / Control, Emit® II Plus Specialty Drug Control Negative and Control Positive are substantially equivalent to the legally marketed predicate devices for their general intended use. Substantial equivalence was demonstrated through comparison of intended use and technological features to the commercially available predicate devices and confirmed by liquid chromatography/ tandem mass spectrometry (LC/MS/MS), a reference analytical method. The information in this pre-market notification provides reasonable assurance that the Emit® II Plus Buprenorphine Assay. Emit® II Plus Specialty Drug Calibrator / Control, Emit® II Plus Specialty Drug Control Negative and Control Positive demonstrate safety and effectiveness similar to the predicate devices - Microgenics CEDIA® Buprenorphine Assay, CEDIA® Buprenorphine Calibrators, and CEDIA® Buprenorphine Controls (cleared under K040316).

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).