The CEDIA Buprenorphine II Assay is a homogeneous enzyme immunoassay for the qualitative and/or semiquantitative determination for the presence of buprenorphine and its metabolites in human urine at a cut-off concentration of 10 ng/ mL. The assay is intended to be used in laboratories and provides a simple and rapid analytical screening procedure to detect buprenorphine and its metabolites in human urine. The assay is designed for use with a number of clinical 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 Liquid chromatography/tandem mass spectrometry (LC-MS/ MS) or permitting laboratories to establish quality control procedures.

The assay provides only a preliminary analytical test result. A more specific alternative chemical must be used to obtain a confirmed analytical result. Gas chromatography/ mass spectrometry (GC/MS) or Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is the preferred confirmatory method.

Clinical and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.

CEDIA Buprenorphine II Calibrators:

The CEDIA Buprenorphine II calibrators and CEDIA Negative Calibrator II are intended for the calibration of the CEDIA Buprenorphine II Assay in human urine. For In Vitro Diagnostic Use Only.

CEDIA Buprenorphine II Control Set:

The CEDIA Buprenorphine II controls are used to validate the CEDIA Buprenorphine II Assay calibration in human urine. For In Vitro Diagnostic Use Only.

Device Description

The assay consists of buffers (1 and 2) and lyophilized reagents (1a and 2a). The components include mouse monoclonal anti-buprenorphine antibody, recombinant microbial "enzyme donor'' - buprenorphine conjugate, "enzyme acceptor", chlorophenol red ß-Dgalactopyranoside, stabilizers and preservatives. Calibrators and controls are sold separately.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the CEDIA Buprenorphine II Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance:

Performance Characteristic	Acceptance Criteria (Implicit/Explicit)	Reported Device Performance (CEDIA Buprenorphine II Assay)
Precision (Qualitative Mode)	-100% to -25% spiked samples: 100% Negative	-100% to -25% spiked samples: 100% Negative (80/80)
	+25% to +100% spiked samples: 100% Positive	+25% to +100% spiked samples: 100% Positive (80/80)
	At 100% cutoff (10 ng/mL): Mix of Negative/Positive results expected around cutoff	At 100% cutoff (10 ng/mL): 27 Negative / 53 Positive (80 determinations)
Precision (Semi-Quantitative Mode)	-100% to -25% spiked samples: 100% Negative	-100% to -25% spiked samples: 100% Negative (80/80)
	+25% to +100% spiked samples: 100% Positive	+25% to +100% spiked samples: 100% Positive (80/80)
	At 100% cutoff (10 ng/mL): Mix of Negative/Positive results expected around cutoff	At 100% cutoff (10 ng/mL): 35 Negative / 45 Positive (80 determinations)
Spike Recovery (Semi-Quantitative)	Spiked 7.5 ng/mL sample: Negative	100% (20/20) Negative
	Spiked 12.5 ng/mL sample: Positive	100% (20/20) Positive
	Recovery within 80-120% of nominal values	Achieved for spiked samples
Analytical Recovery and Dilution Linearity	(Implicit: Acceptable linearity and recovery across range for accurate quantification)	Refer to table for specific levels; e.g., 5 ng/mL - 119.8%, 100 ng/mL - 104.7%
Method Comparison and Accuracy (Qualitative)	(Implicit: High agreement with LC-MS/MS, especially outside near-cutoff zones)	High agreement in "Negative" (<50% cutoff) and "High Positives" (>50% cutoff) categories. Discordant samples detailed.
Method Comparison and Accuracy (Semi-Quantitative)	(Implicit: High agreement with LC-MS/MS, especially outside near-cutoff zones)	High agreement in "Negative" (<50% cutoff) and "High Positives" (>50% cutoff) categories. Discordant samples detailed.
Specificity (Cross-reactivity with Buprenorphine metabolites)	(Implicit: Detect target analytes effectively)	Buprenorphine, Norbuprenorphine, Norbuprenorphine-ß-D-glucuronide: ≥ 100% cross-reactivity. Buprenorphine-ß-D-glucuronide: 76.9% cross-reactivity.
Specificity (Cross-reactivity with other compounds)	(Implicit: Negligible cross-reactivity with structurally related/unrelated opiates and other commonly co-administered drugs)	Negligible cross-reactivity (< 0.01% - < 0.1%) for all tested compounds at high concentrations (e.g., 100,000 ng/mL, 500,000 ng/mL)
Interference (pH and Endogenous Substances)	(Implicit: No significant interference with assay results)	Low and High controls detected accurately across various pH levels and in presence of numerous endogenous substances (e.g., Acetone, Creatinine, Glucose, Hemoglobin)
Interference (Specific Gravity)	(Implicit: No significant interference with assay results)	Low and High controls detected accurately across specific gravity range of 1.000 to 1.030
Open Vial Stability	(Implicit: Maintain performance for claimed duration)	Supports 60 days at 2-8°C for qualitative and semi-quantitative modes
Reagent On-Board Stability	(Implicit: Maintain performance for claimed duration)	Supports 60 days on-board clinical analyzer for qualitative and semi-quantitative modes
Reconstituted Reagent Stability	(Implicit: Maintain performance for claimed duration)	Supports 60 days at 2-8°C for qualitative and semi-quantitative modes
Real Time Stability	(Implicit: Demonstrate long-term stability)	Ongoing, carried out for up to six months.
Accelerated Stability (Reagents, Calibrators, Controls)	(Implicit: Predict long-term stability based on accelerated conditions)	Low and High Controls detected as Negative/Positive respectively for 6 months at 23±2°C (equivalent to 19 months based on 010 math model); recoveries within 80-120%.

2. Sample Sizes and Data Provenance:

Precision Study: n=80 (80 determinations for each spiked concentration)
Analytical Recovery and Dilution Linearity: 10 intermediate levels, each run in replicates of five.
Method Comparison and Accuracy: 153 urine patient samples.
Specificity (Cross-reactivity): Known amounts of analytes added to drug-free urine.
Interference (pH and Endogenous Substances): Known compounds of potentially interfering substances spiked into controls.
Interference (Specific Gravity): Drug-free urine samples with specific gravity ranging from 1.000 to 1.030, spiked with controls.
Stability Studies: Two lots for open vial, on-board, and reconstituted reagent stability. Three lots for real-time and accelerated stability.

Data Provenance: Not explicitly stated in terms of country of origin. The study appears to be retrospective as it uses "urine patient samples" and "drug-free urine," implying previously collected samples, but it doesn't definitively state whether they were specifically collected for this study (prospective) or were pre-existing (retrospective). Given the context of 510(k) submissions, retrospective data is common for analytical validation using clinical specimens.

3. Number of Experts and their Qualifications for Ground Truth:

Method Comparison and Accuracy: The ground truth for the 153 urine patient samples was established using LC-MS/MS (Liquid chromatography/tandem mass spectrometry).
Number of Experts/Qualifications: The document does not specify the number of experts or their qualifications for interpreting the LC-MS/MS results. LC-MS/MS is a highly precise analytical method, and its results are generally considered the "gold standard" or definitive ground truth in toxicology. The interpretation of these results is typically performed by trained laboratory personnel.

4. Adjudication Method:

Not applicable as the ground truth is established by a definitive analytical method (LC-MS/MS), not by expert consensus or adjudication of subjective interpretations.

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

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay (laboratory test), not an imaging AI or diagnostic support system where human readers interpret results. The performance is evaluated analytically against a gold standard method.

6. Standalone (Algorithm Only) Performance:

Yes, the study primarily describes standalone performance. The "Immunoassay Results" (both qualitative and semi-quantitative) are compared directly against the LC-MS/MS ground truth. There is no human-in-the-loop performance described. The device, an enzyme immunoassay, operates as a standalone analytical system.

7. Type of Ground Truth Used:

The primary ground truth used for performance validation is definitive analytical method results, specifically LC-MS/MS (Liquid chromatography/tandem mass spectrometry), which is considered highly accurate for drug quantification in urine.

8. Sample Size for the Training Set:

The document does not provide information on the sample size used for the training set. This is typical for a 510(k) submission for an IVD device like this, as the validation data presented ("Summary of Supporting Data") focuses on the final product's performance against a test set, rather than the development or training of the assay itself. The assay's development likely involved iterative testing and optimization, but specific training set sizes are not disclosed here.

9. How the Ground Truth for the Training Set was Established:

As the training set information is not provided, the method for establishing its ground truth is also not described in this document.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002 April 6. 2017

MICROGENICS CORPORATION MINOTI PATEL SR. REGULATORY AFFAIRS SPECIALIST 46500 KATO ROAD FREMONT CA 94538

Re: K163101 Trade/Device Name: CEDIA Buprenorphine II Assay CEDIA Buprenorphine II Calibrators and CEDIA Negative Calibrator II CEDIA Buprenorphine II Control Set Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate test system Regulatory Class: II Product Code: DJG, DLJ, LAS Dated: March 17, 2017 Received: March 20, 2017

Dear Minoti Patel:

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

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

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting 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

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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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Indications for Use

510(k) Number (if known) K163101

Device Name CEDIA Buprenorphine II Assay CEDIA Buprenorphine II Calibrators and CEDIA Negative Calibrator II CEDIA Buprenorphine II Control Set

Indications for Use (Describe)

CEDIA Buprenorphine II Assay:

Clinical and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.

CEDIA Buprenorphine II Calibrators:

The CEDIA Buprenorphine II calibrators and CEDIA Negative Calibrator II are intended for the calibration of the CEDIA Buprenorphine II Assay in human urine. For In Vitro Diagnostic Use Only.

CEDIA Buprenorphine II Control Set:

The CEDIA Buprenorphine II controls are used to validate the CEDIA Buprenorphine II Assay calibration in human urine. For In Vitro Diagnostic Use Only.

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

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Summary

A. Device InformationCategory	Comments
Sponsor:	Microgenics CorporationThermo Fisher Scientific46500 Kato RoadFremont, CA 94538Phone: 510-979-5000FAX: 510-979-5002
Correspondent ContactInformation:	Minoti Patel, RACSr. Regulatory Affairs SpecialistEmail: Minoti.patel@thermofisher.comPhone: 510-749-5000FAX: 510-749-5002
Device Common Name:	Buprenorphine Immunoassay Test System
Trade or Proprietary Name	CEDIA® Buprenorphine II AssayCEDIA® Buprenorphine II CalibratorsCEDIA® Negative Calibrator IICEDIA® Buprenorphine II Control Set
Predicate Device ProductCode, Classification,Classification Name & Panel	DJG, Class II, 21 CFR 862.3650 – Opiate test system,91 - ToxicologyDLJ, Class II, 21 CFR 862.3200 – Clinical toxicologycontrol material, 91 – ToxicologyLAS, Class I, reserved; 21 CFR 862.3280 – Clinicaltoxicology control material. 91 - Toxicology

A. Device Information

Predicate Device Information:

Predicate Device:	CEDIA® Buprenorphine AssayCEDIA® Negative Calibrator IICEDIA® Buprenorphine CalibratorsCEDIA® Buprenorphine Control Set
Predicate DeviceManufacturer:	Microgenics Corporation
Predicate Device CommonName:	Buprenorphine Immunoassay Test System
Predicate Device PremarketNotification #:	K040316
Predicate Device ProductCode, Classification,Classification Name & Panel	DJG, Class II, 21 CFR 862.3650 – Opiate test system,91 - ToxicologyDLJ, Class II, 21 CFR 862.3200 – Clinical toxicologycontrol material, 91 – ToxicologyLAS, Class I, reserved; 21 CFR 862.3280 – Clinicaltoxicology control material. 91 - Toxicology

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B. Date Summary Revised

April 04, 2017

C. Description of Device

D. Intended Use

Intended Use:

CEDIA® Buprenorphine II Assay:

The CEDIA® Buprenorphine II Assay is a homogeneous enzyme immunoassay for the qualitative and/or semiquantitative determination for the presence of buprenorphine and its metabolites in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a simple and rapid analytical screening procedure to detect buprenorphine and its metabolites in human urine. The assay is designed for use with a number of clinical 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 Liquid chromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establish quality control procedures.

The assay provides only a preliminary analytical test result. A more specific alternative chemical method must be used to obtain a confirmed analytical result. Gas chromatography/ mass spectrometry (GC/MS) or Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is the preferred confirmatory method.

Clinical and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.

CEDIA® Buprenorphine II Calibrators:

The CEDIA® Buprenorphine II calibrators and CEDIA® Negative Calibrator II are intended for the calibration of the CEDIA® Buprenorphine II Assay in human urine. For In Vitro Diagnostic Use Only.

CEDIA® Buprenorphine II Control Set:

The CEDIA® Buprenorphine II controls are used to validate the CEDIA® Buprenorphine II Assay calibration in human urine. For In Vitro Diagnostic Use Only.

E. Comparison to Predicate Device

Both devices use similar reagent and instrument systems. Both devices detect buprenorphine. The predicate device's specific antibody detects buprenorphine and buprenorphine glucuronide at cutoff concentration of 5 ng/mL. The CEDIA device's specific antibody detects buprenorphine, buprenorphine glucuronide, norbuprenorphine and norbuprenorphine

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glucuronide at a buprenorphine cutoff concentration of 10 ng/ml. Other differences and similarities are presented below.

Similarities - Assay
Item	Device	K040316 - MicrogenicsCEDIA BuprenorphineAssay
Intended Use	Same	Detection ofbuprenorphine in humanurine
Methodology	Same	CEDIA (Cloned EnzymeDonor Immunoassay)
Intended Users	Same	Prescription users only
Reagents Form	Same	Lyophilized (requiringreconstitution) and liquidready to use
Antibody	Same	Mouse monoclonal
Storage	Same	2 – 8° C until expirationdate
Target Analyte	Same	Buprenorphine

Differences - Assay
Item	Device	Predicate
Cutoff	10 ng/mL	5 ng/mL

Similarities – Calibrators
Item	Device	Predicate
Form	Same	Liquid – ready to use
Storage	Same	2–8° C until expiration date

Differences - Calibrators
Item	Device	Predicate
Calibrator Name	CEDIA®Buprenorphine II calibrators and controls	CEDIA®Buprenorphine calibrators and controls
Calibrator Levels	0, 10, 20, 50, 100 ng/mL	0, 5, 20, 50, 75 ng/mL

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Similarities – Controls
Item	Device	Predicate
Form	Same	Liquid – ready to use
Storage	Same	2 – 8° C until expirationdate

Item	Device	Predicate
Control Names	CEDIA®Buprenorphine II controls	CEDIA®Buprenorphine controls
Control Levels	7.5 and 12.5 ng/mL	3 and 7 ng/mL
Form	Same	Liquid - ready to use
Storage	Same	2 – 8° C untilexpiration date

F. Test Principle

The assay is based on bacterial enzyme ß-galactosidase genetically engineered to two inactive fragments, one of which is conjugated to buprenorphine. Buprenorphine in the sample competes with the enzyme fragment-conjugated buprenorphine for binding to antibuprenorphine antibody. In the absence of buprenorphine in the sample, the fragment binds antibody and does not re-associate to form active enzyme. If buprenorphine is present in the sample it binds to the antibody, allowing the enzyme fragments to re-associate. The reassociated enzyme cleaves the substrate, generating a color change that can be measured spectrophotometrically (570/660 nm). The amount of active enzyme is proportional to the analyte present.

G. Summary of Supporting Data

1. Analytical Performance:

Performance is evaluated at the manufacturer's site on Beckman Coulter AU 680 Analyzer.

a) Precision Study is performed for two runs per day, twice a day, for 20 days (total n=80). Samples are prepared by spiking Buprenorphine into drug free urine at the cutoff, 25%, 50%, 75% & 100% above and below the cutoff and tested in both qualitative and semi-quantitative modes. Representative data is presented below.

% ofCutoff	Spiked Conc.(ng/mL)	LC-MS/MS(ng/mL)	Within Run (n=80)
			Number ofdeterminants	ImmunoassayResults
-100%	0	0	80	80 Neg
-75%	2.5	2.99	80	80 Neg
-50%	5	5.31	80	80 Neg
-25%	7.5	7.63	80	80 Neg
100%	10	10.99	80	27 Neg/53 Pos
+25%	12.5	12.97	80	80 Pos

Oualitative Results:

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% ofCutoff	Spiked Conc.(ng/mL)	LC-MS/MS(ng/mL)	Within Run (n=80)
			Number of determinants	Immunoassay Results
+50%	15	15.05	80	80 Pos
+75%	17.5	18.92	80	80 Pos
+100%	20	20.38	80	80 Pos

Semi-Quantitative Results:

% ofCutoff	Spiked Conc.(ng/mL)	LC-MS/MS(ng/mL)	Within Run (n=80)
			Number ofdeterminants	ImmunoassayResults
-100%	0	0	80	80 Neg
-75%	2.5	2.99	80	80 Neg
-50%	5	5.31	80	80 Neg
-25%	7.5	7.63	80	80 Neg
100%	10	10.99	80	35 Neg/45 Pos
+25%	12.5	12.97	80	80 Pos
+50%	15	15.05	80	80 Pos
+75%	17.5	18.92	80	80 Pos
+100%	20	20.38	80	80 Pos

b) Spike Recovery All 20 replicates of spiked 7.5 ng/mL and 12.5 ng/mL sample detect as Negative and Positive, respectively, when compared to 10 ng/mL spiked sample.
In semi-quantitative mode, the spiked samples recover within 80-120% of the nominal values.
c) Analytical Recovery and Dilution Linearity To demonstrate the dilution linearity for purpose of sample dilution and quality control of the entire assay range, drug free urine is spiked to the high calibrator level of Buprenorphine (100 ng/mL) and diluted with drug free urine to generate 10 intermediate levels.
Each sample is run in replicates of five in semi-quantitative mode and the average is used to determine percent recovery compared to the expected target value. Representative data is presented below.

Level	TargetConcentration(ng/mL)	ObservedConcentration(ng/mL)	Recovery (%)
1	0	-0.09	n/a
2	5	5.99	119.8
3	10	10.97	109.7
4	20	19.66	98.3
5	30	33.03	110.1
6	40	43.83	109.6

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Level	TargetConcentration(ng/mL)	ObservedConcentration(ng/mL)	Recovery (%)
7	50	52.98	106.0
8	60	67.28	112.1
9	70	77.54	110.8
10	80	85.14	106.4
11	90	95.38	106.0
12	100	104.70	104.7

d) Method Comparison and Accuracy One hundred and fifty three urine patient samples are analyzed by the CEDIA® Buprenorphine II Assay in both qualitative and semiquantitative modes and the results are compared to LC-MS/MS.
Qualitative mode using stratified Buprenorphine values by LC-MS/MS

CandidateDeviceResults	Negative	<50% ofCutoffconcentrationby LC-MS/MS(<5ng/mL)	Near CutoffNegative(Between50% belowthe cutoffconcentrationasdeterminedby LC-MS/MS)(5-9.9ng/mL)	Near CutoffPositive(Between thecutoff and50% abovethe cutoffconcentrationas determinedby LC-MS/MS)(10-15ng/mL)	HighPositives(Greater than50% abovecutoffconcentration)(>15ng/mL)
Positive	31*	11*	4*	5	45
Negative	49	2	6	0	0

Discordant samples summarized in table 5 below.

Semi-Quantitative mode using stratified Buprenorphine values by LC-MS/MS

CandidateDeviceResults	Negative	<50% ofCutoffconcentrationby LC-MS/MS(<5ng/mL)	Near CutoffNegative(Between50% belowthe cutoffconcentrationasdeterminedby LC-MS/MS)(5-9.9ng/mL)	Near CutoffPositive(Between thecutoff and50% abovethe cutoffconcentrationas determinedby LC-MS/MS)(10-15ng/mL)	HighPositives(Greater than50% abovecutoffconcentration)(>15ng/mL)
Positive	32*‡	11*	4*	5	45
Negative	48	2	6	0	0

Discordant samples summarized in table 5 below.

Additional discordant sample (ID #53) in Lot #3 Semi-quantitative mode shown in table 5 below.

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*Table for Discordant Samples

		EIA	LC-MS/MS Concentration (ng/mL)
SampleID	Qualmode	SQ(ng/mL)	Bup***	NorBup#	Bup-Glu	NorBup-Glu†	Total byLC-MS/MS
51	Pos	10.08	<LLOQ**	2.27	1.96	6.18	10.41
52	Pos	10.02	<LLOQ	0.69	3.15	6.84	10.68
53‡	Neg	10.42	<LLOQ	1.08	7.89	1.82	10.79
54	Pos	11.59	<LLOQ	1.09	5.67	5.54	12.30
55	Pos	10.40	<LLOQ	3.27	2.54	7.92	13.73
56	Pos	16.36	<LLOQ	4.02	7.46	3.73	15.21
57	Pos	17.31	<LLOQ	3.28	10.67	3.09	17.04
58	Pos	19.82	<LLOQ	5.03	10.91	2.05	17.99
59	Pos	18.73	<LLOQ	3.10	9.09	6.59	18.78
60	Pos	22.63	<LLOQ	4.18	8.30	7.34	19.82
61	Pos	18.95	<LLOQ	1.96	9.90	9.90	21.76
62	Pos	26.11	<LLOQ	4.36	10.87	6.92	22.15
63	Pos	24.99	<LLOQ	5.26	8.41	9.01	22.68
64	Pos	24.91	<LLOQ	3.86	23.19	<LLOQ	27.05
65	Pos	20.87	<LLOQ	1.44	14.06	14.06	29.56
66	Pos	23.21	<LLOQ	2.23	25.24	2.50	29.97
67	Pos	30.27	<LLOQ	4.42	8.82	16.84	30.08
68	Pos	31.35	<LLOQ	16.52	9.41	5.47	31.40
69	Pos	35.38	<LLOQ	7.13	5.30	22.38	34.81
70	Pos	40.38	<LLOQ	12.21	18.65	9.11	39.97
71	Pos	38.44	<LLOQ	2.93	12.40	28.84	44.17
72	Pos	48.60	<LLOQ	23.41	15.34	5.44	44.19
73	Pos	62.31	<LLOQ	5.47	36.52	25.00	66.99
74	Pos	81.31	<LLOQ	33.59	23.42	12.72	69.73
75	Pos	88.67	<LLOQ	26.22	32.43	23.10	81.75
76	Pos	79.26	<LLOQ	6.34	80.00	2.77	89.11
77	Pos	>100.01	<LLOQ	8.63	56.89	46.95	112.47
78	Pos	>100.01	<LLOQ	101.98	10.40	9.90	122.28
79	Pos	>100.01	<LLOQ	7.91	26.43	144.00	178.34
80	Pos	>100.01	<LLOQ	49.66	97.61	121.12	268.39
81	Pos	>100.01	<LLOQ	<LLOQ	145.72	394.81	540.53
82	Pos	>100.01	<LLOQ	129.95	105.07	664.47	899.49

Accuracy samples were categorized based upon the LC-MS/MS concentration for Buprenorphine only. The table below identifies those samples with Buprenorphine concentration below the cutoff, in which the observed CEDIA Buprenorphine II assay result was positive.

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	EIA		LC-MS/MS Concentration (ng/mL)
SampleID	Qualmode	SQ(ng/mL)	Bup***	NorBup#	Bup-Glu+	NorBup-Glut	Total byLC-MS/MS
83	Pos	>100.01	0.81	32.14	39.52	59.14	131.61
84	Pos	63.54	0.86	7.41	29.46	31.38	69.11
85	Pos	20.48	0.90	5.42	11.54	<LLOQ	17.86
86	Pos	>100.01	0.91	54.00	18.10	10.52	83.53
87	Pos	46.32	2.00	12.03	13.58	16.24	43.85
88	Pos	>100.01	2.00	6.83	193.42	131.65	333.90
89	Pos	>100.01	2.02	75.75	174.74	442.98	695.49
90	Pos	66.32	2.48	6.53	57.67	1.52	68.20
91	Pos	>100.01	3.63	80.26	733.7	624.02	1441.61	92	Pos	>100.01	4.38	69.28	146.16	349.33	569.15	93	Pos	>100.01	4.45	59.03	55.01	17.31	135.80	100	Pos	>100.01	8.64	36.91	>ULOQ**	224.42	>1000	101	Pos	>100.01	8.94	51.32	497.32	55.06	612.64	102	Pos	>100.01	5.22	35.13	85.99	22.24	148.58	103	Pos	77.36	6.60	147.58	195.67	40.28	390.13
91	Pos	>100.01	3.63	80.26	733.7	624.02	1441.61
92	Pos	>100.01	4.38	69.28	146.16	349.33	569.15
93	Pos	>100.01	4.45	59.03	55.01	17.31	135.80
100	Pos	>100.01	8.64	36.91	>ULOQ**	224.42	>1000
101	Pos	>100.01	8.94	51.32	497.32	55.06	612.64
102	Pos	>100.01	5.22	35.13	85.99	22.24	148.58
103	Pos	77.36	6.60	147.58	195.67	40.28	390.13

** <LLOQ: Lower Limit of Quantitation (0.65 ng/mL), >ULOQ: Upper Limit of Quantitation (1000ng/mL);

*** Bup: Buprenorphine;

NorBup: Norbuprenorphine;

Bup-Glu: Buprenorphine-ß-D-glucuronide;
NorBup-Glu: Norbuprenorphine-ß-D-glucuronide;

Additional discordant sample for Lot #3 Semi-Quantitative mode

e) Specificity The cross-reactivity of Buprenorphine and its metabolites is evaluated by adding known amounts of each analyte to drug-free negative urine. As indicated by the results in the table below, Buprenorphine, Norbuprenorphine and Norbuprenorphine-B-Dglucuronide exhibit ≥ 100% cross-reactivity. Buprenorphine-ß-D-glucuronide showed 76.9% cross-reactivity.

Buprenorphine and its metabolites	Tested Concentration(ng/mL)	Positive/Negative	Cross-reactivity(%)
Buprenorphine	10	Positive	100
Norbuprenorphine	8	Positive	125
Buprenorphine-β-D-glucuronide	13	Positive	76.9
Norbuprenorphine-β-D-glucuronide	10	Positive	100
Structurally Related Compounds andOther Opiates	Tested Concentration(ng/mL)	Positive/Negative	Cross-reactivity (%)
6-Acetyl morphine	100,000	Negative	< 0.01
Diacetylmorphine (Heroin)	100,000	Negative	< 0.01
Codeine	100,000	Negative	< 0.01
Dextromethorphan	100,000	Negative	< 0.01
Dihydrocodeine	100,000	Negative	< 0.01
EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine)	100,000	Negative	< 0.01
EMDP (2-Ethyl-5-methyl-3,3-diphenylpyrroline)	100,000	Negative	< 0.01
Fentanyl	100,000	Negative	< 0.01
Hydrocodone	100,000	Negative	< 0.01
Hydromorphone	100,000	Negative	< 0.01
Hydromorphone-β-D-glucuronide	10,000	Negative	< 0.1
LAAM (Levo-alpha-acetylmethadol)	100,000	Negative	< 0.01
Levorphanol	100,000	Negative	< 0.01
Methadone	100,000	Negative	< 0.01
Meperidine	100,000	Negative	< 0.01
Morphine	100,000	Negative	< 0.01
Morphine-3B-D-glucuronide	100,000	Negative	< 0.01
Morphine-6β-D-glucuronide	100,000	Negative	< 0.01
Nalorphine	100,000	Negative	< 0.01
Naloxone	100,000	Negative	< 0.01
Naltrexone	100,000	Negative	< 0.01
Norcodeine	100,000	Negative	< 0.01
Norhydrocodone	100,000	Negative	< 0.01
Norpropoxyphene	100,000	Negative	< 0.01
Noroxycodone	100,000	Negative	< 0.01
Noroxymorphone	100,000	Negative	< 0.01
Oxymorphone-β-D-glucuronide	10,000	Negative	< 0.1
Oxycodone	100,000	Negative	< 0.01
Oxymorphone	100,000	Negative	< 0.01
Tapentadol	100,000	Negative	< 0.01
Tramadol	100,000	Negative	< 0.01

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Cross Reactivity of Structurally Related or Unrelated Opiate Compounds

The potential cross-reactivity posed by drugs commonly co-administered with Buprenorphine is evaluated by adding each substance to Buprenorphine spiked at Low Control (7.5 ng/mL) and High Control (12.5 ng/mL) levels at the concentrations indicated. A drug is considered to crossreact if the observed Buprenorphine concentrations result exceed 10 ng/mL. As shown in the table below, all the pharmacologic compounds evaluated exhibited negligible cross reactivity at the concentrations tested.

{12}------------------------------------------------

Compound	Tested Concentration (ng/mL)	Spiked Buprenorphine Level
	Low Control	High Control
Negative Urine	0	Negative	Positive
Acetaminophen	500,000	Negative	Positive
Acetylsalicylic acid	500,000	Negative	Positive
Amitryptyline	50,000	Negative	Positive
Amoxicillin	100,000	Negative	Positive
Amphetamine	1,000,000	Negative	Positive
Amisulpride	100,000	Negative	Positive
Benzoylecgonine	1,000,000	Negative	Positive
Caffeine	100,000	Negative	Positive
Carbamazepine	100,000	Negative	Positive
Chlorpromazine	100,000	Negative	Positive
Clomipramine	25,000	Negative	Positive
Chloroquine	100,000	Negative	Positive
Cimetidine	500,000	Negative	Positive
Desipramine	10,000	Negative	Positive
Doxepine	25,000	Negative	Positive
Diphenylhydramine	100,000	Negative	Positive
Ephedrine	100,000	Negative	Positive
Fluoxethine	100,000	Negative	Positive
Fluphenazine	100,000	Negative	Positive
Hydroxychloroquine	100,000	Negative	Positive
Ibuprofen	100,000	Negative	Positive
Imipramine	25,000	Negative	Positive
Maprotiline	100,000	Negative	Positive
Mitragynine	100,000	Negative	Positive
7-OH Mitragynine	10,000	Negative	Positive
Nalbuphine	100,000	Negative	Positive
Nortryptiline	50,000	Negative	Positive
Oxazepam	100,000	Negative	Positive
Phencyclidine	100,000	Negative	Positive
Phenobarbital	100,000	Negative	Positive
Ranitidine	500,000	Negative	Positive
Secobarbital	100,000	Negative	Positive
Sulpiride	100,000	Negative	Positive
Thioridazine	100,000	Negative	Positive
Trimipramine	25,000	Negative	Positive

Structurally Unrelated Compounds Spiked at the Concentration Listed Below into Low Control and High Control

f) Interference The potential interference of pH and endogenous physiologic substances on recovery of Buprenorphine using CEDIA® Buprenorphine II Assay is assessed by spiking known compounds of potentially interfering substances into the Low Control (7.5 ng/mL) and High Control (12.5 ng/mL). In the presence of the compounds listed below, the controls are detected accurately, indicating that these compounds did not show interference in the assay.

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Compound	Tested Concentration (mg/dL)	Spiked Buprenorphine Level
		Low Control	High Control
Negative Urine	0	Negative	Positive
Acetaminophen	10	Negative	Positive
Acetone	500	Negative	Positive
Acetyl Salicylic Acid	10	Negative	Positive
Ascorbic Acid	150	Negative	Positive
Caffeine	10	Negative	Positive
Creatinine	400	Negative	Positive
Ethanol	10	Negative	Positive
Galactose	5	Negative	Positive
Glucose	1000	Negative	Positive
Hemoglobin	150	Negative	Positive
Human Serum Albumin	200	Negative	Positive
Ibuprophen	10	Negative	Positive
Oxalic acid	50	Negative	Positive
Riboflavin	3	Negative	Positive
Sodium Chloride	1000	Negative	Positive
Urea	1000	Negative	Positive
pH
pH	3	Negative	Positive
pH	4	Negative	Positive
pH	5	Negative	Positive
pH	6	Negative	Positive
pH	7	Negative	Positive
pH	8	Negative	Positive
pH	9	Negative	Positive
pH	10	Negative	Positive
pH	11	Negative	Positive

Specific Gravity - Drug free urine samples with specific gravity ranging in value within 1.000 to 1.030 are split and spiked to a final concentration of either 7.5 ng/mL or 12.5 ng/mL (the Low Control and High Control concentrations, respectively). These samples are then evaluated in both qualitative and semi-quantitative modes. No interference is observed.

	Spiked Buprenorphine Concentration
Specific Gravity	Low Control	High Control
1.002	Negative	Positive
1.004	Negative	Positive
1.008	Negative	Positive
1.013	Negative	Positive
1.016	Negative	Positive
1.018	Negative	Positive

{14}------------------------------------------------

	Spiked Buprenorphine Concentration
Specific Gravity	Low Control	High Control
1.022	Negative	Positive
1.023	Negative	Positive
1.025	Negative	Positive
1.030	Negative	Positive

g) Stability

Open Vial Stability:

Open Vial stability studies for two lots stored at 2-8°C supports the claim of 60 days for qualitative and semi-quantitative modes.

Reagent On-Board Stability:

Reagent On-Board stability studies for two lots stored on-board clinical analyzer supports the claim of 60 days for qualitative and semi-quantitative modes.

Reconstituted Reagent Stability:

Reconstituted Reagent stability studies for two lots stored at 2-8°C supports the claim of 60 days for qualitative and semi-quantitative modes.

Real Time Stability for Reagent, Calibrators and Controls

Real time stability studies for three lots of reagents, calibrators and controls stored at 2-8°C are ongoing and have been carried out for up to six months.

Accelerated Stability Results for Reagents, Calibrators and Controls

Accelerated stability testing results show that the Low Control is detected as negative and the High Control is detected as positive for each time point for a period of six months at 23°+2°C. This is equivalent to 19 months of stability based on 010 math model. The recoveries of the Low Control and High Control are within 80–120%. The data for six month accelerated stability confirms that the Low Control and the High Control are detected as negative and positive, respectively.

H. Conclusion

Comparison of CEDIA® Buprenorphine II Assay, Calibrators, Controls and CEDIA® Negative Calibrator II and predicate devices demonstrated that the technological characteristics and intended use are substantially equivalent to the currently marketed predicate devices, CEDIA® Buprenorphine Assay, (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).