Who is the manufacturer of CEDIA Heroin Metabolite (6-AM) Assay?

Microgenics Corporation filed the 510(k) submission for CEDIA Heroin Metabolite (6-AM) Assay (K173183).

What is the FDA product code for CEDIA Heroin Metabolite (6-AM) Assay?

DJG. It is classified under 21 CFR 862.3650 as a Class 2 device in the Clinical Toxicology panel.

What is the regulatory pathway for CEDIA Heroin Metabolite (6-AM) Assay?

510(k) clearance (submission type: Traditional).

Who can help prepare an FDA 510(k) submission like CEDIA Heroin Metabolite (6-AM) Assay?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA 510(k) submissions. See https://innolitics.com/services/510ks/ or contact https://innolitics.com/contact.

CEDIA Heroin Metabolite (6-AM) Assay

K173183 · Microgenics Corporation · DJG · Nov 22, 2017 · Clinical Toxicology

Device Facts

Record ID	K173183
Device Name	CEDIA Heroin Metabolite (6-AM) Assay
Applicant	Microgenics Corporation
Product Code	DJG · Clinical Toxicology
Decision Date	Nov 22, 2017
Decision	SESE
Submission Type	Traditional
Regulation	21 CFR 862.3650
Device Class	Class 2

Intended Use

The CEDIA Heroin Metabolite (6-Acetylmorphine, or 6-AM) Assay is a homogeneous enzyme immunoassay for the in vitro qualitative and/or semi-quantitative determination of the presence of heroin metabolite (6-AM) in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a rapid analytical screening procedure to detect 6-Acetylmorphine in human urine. The assay is designed for use with a number of clinical chemistry analyzers. This product is intended to be used by trained professionals only. 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/ 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.

Device Story

Homogeneous enzyme immunoassay; detects 6-Acetylmorphine (6-AM) in human urine. Input: urine sample; Reagents: mouse monoclonal antibodies, recombinant microbial enzyme donor (ED)-6-AM conjugate, enzyme acceptor (EA), chlorophenol red-beta-D-galactopyranoside. Principle: EA and ED fragments re-associate to form active enzyme; enzyme cleaves substrate to produce color change measured spectrophotometrically. Used in clinical laboratories by trained professionals. Output: qualitative (positive/negative) or semi-quantitative concentration result. Results serve as preliminary screen; require confirmation via GC/MS or LC-MS/MS. Clinical decision-making relies on professional judgment; aids in identifying heroin use.

Clinical Evidence

Bench testing only. Performance evaluated on Beckman Coulter AU 680 analyzer. Precision (n=80) showed 100% agreement at +/- 25% of cutoff. Method comparison (n=100) against LC-MS/MS demonstrated 99% overall concordance. Specificity testing confirmed 100% cross-reactivity for 6-AM and negligible cross-reactivity for structurally related/unrelated compounds. Interference studies evaluated pH, specific gravity, and endogenous substances; pH 11 was identified as an interferent.

Technological Characteristics

Homogeneous enzyme immunoassay; utilizes recombinant DNA technology (beta-galactosidase fragments). Reagents: mouse monoclonal antibodies, ED-6-AM conjugate, EA, chlorophenol red-beta-D-galactopyranoside. Form: Lyophilized reagents (reconstitution required). Connectivity: Designed for use with clinical chemistry analyzers. Storage: 2-8°C.

Indications for Use

Indicated for in vitro qualitative and/or semi-quantitative screening of heroin metabolite (6-AM) in human urine at 10 ng/mL cutoff. Intended for use by trained laboratory professionals on clinical chemistry analyzers. Requires confirmatory testing (GC/MS or LC-MS/MS) for positive results.

Regulatory Classification

Identification

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

Special Controls

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

Predicate Devices

CEDIA DAU 6-Acetylmorphine Assay (k001178)

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Submission Summary (Full Text)

{0}------------------------------------------------ Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue. November 22, 2017 Microgenics Corporation Minoti Patel Manager, Regulatory Affairs 46500 Kato Road Fremont, California 94538 Re: K173183 Trade/Device Name: CEDIA Heroin Metabolite (6-AM) Assay Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate test system Regulatory Class: Class II Product Code: DJG Dated: September 28, 2017 Received: October 2, 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 Part 801 and Part 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 {1}------------------------------------------------ Part 820); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance. For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100). Sincerely, Stayce Beck -A For: 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 {2}------------------------------------------------ # Indications for Use 510(k) Number (if known) K173183 Device Name CEDIA Heroin Metabolite (6-AM) Assay #### Indications for Use (Describe) CEDIA Heroin Metabolite (6-AM) Assay: The CEDIA Heroin Metabolite (6-Acetylmorphine, or 6-AM) Assay is a homogeneous enzyme immunoassay for the in vitro qualitative and/or semi-quantitative determination of the presence of heroin metabolite (6-AM) in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a rapid analytical screening procedure to detect 6-Acetylmorphine in human urine. The assay is designed for use with a number of clinical chemistry analyzers. This product is intended to be used by trained professionals only. 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/ 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. | Type of Use (Select one or both, as applicable) | | |--------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------| | <div style="display:inline-block;"> Prescription Use (Part 21 CFR 801 Subpart D)</div> | <div style="display:inline-block;"> Over-The-Counter Use (21 CFR 801 Subpart C)</div> | #### CONTINUE ON A SEPARATE PAGE IF NEEDED. This section applies only to requirements of the Paperwork Reduction Act of 1995. #### *DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.* The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to: > Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov "An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number." {3}------------------------------------------------ # k173183 # 510(k) Summary 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. #### A. Device Information | Category | Comments | |----------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------| | Sponsor: | Microgenics Corporation Thermo Fisher Scientific 46500 Kato Road Fremont, CA 94538 Phone: 510-979-5000 FAX: 510-979-5002 | | Correspondent Contact Information: | Minoti Patel, RAC Manager, Regulatory Affairs Email: Minoti.patel@thermofisher.com Phone: 510-979-5000 FAX: 510-979-5002 | | Device Common Name: | 6-Acetylmorphine Immunoassay Test System | | Trade or Proprietary Name | CEDIA Heroin Metabolite (6-AM) Assay | | Candidate Device Product Code, Classification, Classification,Name & Panel | DJG, Class II, 21 CFR 862.3650 – Opiate test system, 91 – Toxicology | #### Predicate Device Information: | Predicate Device: | CEDIA DAU 6-AcetylmorphineAssay | |-----------------------------------------------|---------------------------------| | Predicate Device Manufacturer: | Microgenics Corporation | | Predicate Device Premarket Notification #: | k001178 | # B. Date Summary Prepared November 21, 2017 {4}------------------------------------------------ ## C. Description of Device The assay consists of buffers (1 and 2) and Ivophilized reagents (1a and 2a). The components include mouse monoclonal antibodies to 6-Acetylmorphine, recombinant microbial enzyme donor (ED) – 6-Acetylmorphine conjugate: enzyme acceptor (EA), chlorophenol red 3-D-galactopyranoside; stabilizers and preservatives. Calibrators and controls are sold separately. #### D. Intended Use #### CEDIA Heroin Metabolite (6-AM) Assay The CEDIA Heroin Metabolite (6-Acetylmorphine, or 6-AM) Assay is a homogeneous enzyme immunoassay for the in vitro qualitative and/or semi-quantitative determination of the presence of heroin metabolite (6-AM) in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a rapid analytical screening procedure to detect 6-Acetylmorphine in human urine. The assay is designed for use with a number of clinical chemistry analyzers. This product is intended to be used by trained professionals only. 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/ 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. | Characteristic | Predicate Device: CEDIA DAU 6-Acetylmorphine Assay (k001178) | Candidate Device: CEDIA Heroin Metabolite (6-AM) Assay | |----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------| | Intended Use | A homogeneous enzyme immunoassay for the in vitro qualitative or semi-quantitative determination of 6- Acetylmorphine in human urine at a cut-off concentration of 10 ng/mL | Same | | Operating | CEDIA | Same | ## E. Comparison to Predicate Device {5}------------------------------------------------ | Characteristic | Predicate Device: CEDIA DAU 6-Acetylmorphine Assay (k001178) | Candidate Device: CEDIA Heroin Metabolite (6-AM) Assay | |---------------------------|--------------------------------------------------------------------|----------------------------------------------------------------------------------------------| | Principle (Technology) | | | | Measured Analyte | Heroin and 6-Acetylmorphine | Same | | Test Matrix | Urine | Same | | Cutoff Levels | 10 ng/mL | Same | | Methodology | Homogeneous Enzyme Immunoassay | Same | | Reagents Form | EA and ED: liquid ready-to-use. | EA and ED: Lyophilized (Reconstitution Required) EARB and EDRB liquid ready-to-use. | | Antibody | Mouse Monoclonal antibody | Same | | Storage | 2-8°C until expiration date. | Same | | Principal Operator | Trained professionals | Same | # F. Test Principle The CEDIA Heroin Metabolite Assay uses recombinant DNA technology to produce a homogeneous enzyme immunoassay system. This assay is based on the bacterial enzyme ß-galactosidase, which has been genetically engineered into two inactive fragments. These fragments, termed Enzyme Acceptor (EA) and Enzyme Donor (ED) spontaneously re-associate to form a fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically. ## G. Summary of Supporting Data ## 1. Analytical Performance: Performance was evaluated at the manufacturer's site on Beckman Coulter AU 680 Analyzer. ## a) Precision Precision studies were performed in accordance with CLSI Guideline EP05-A3. The study was performed for two runs per day, twice a day, for 20 days (total n=80). Samples were prepared by spiking 6-Acetylmorphine methanol stock solution 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. The results are summarized in the tables below. {6}------------------------------------------------ | % of Cutoff | Spiked Conc. (ng/mL) | GC/MS (ng/mL) | Within Run (n=80) | | |-------------|-------------------------|------------------|---------------------------|-----------------------------| | | | | Number of determinants | Immunoassay Results | | -100% | 0 | N/A | 80 | 80 Negative | | -75% | 2.5 | 2.67 | 80 | 80 Negative | | -50% | 5 | 5.17 | 80 | 80 Negative | | -25% | 7.5 | 7.82 | 80 | 80 Negative | | 100% | 10 | 10.2 | 80 | 56 Negative/ 24 Positive | | +25% | 12.5 | 12.8 | 80 | 80 Positive | | +50% | 15 | 15.2 | 80 | 80 Positive | | +75% | 17.5 | 18.0 | 80 | 80 Positive | | +100% | 20 | 21.5 | 80 | 80 Positive | #### Qualitative Results: #### Semi-Quantitative Results: | % of Cutoff | Spiked Conc. (ng/mL) | GC/MS (ng/mL) | Within Run (n=80) | | |-------------|----------------------------|------------------|---------------------------|-----------------------------| | | | | Number of determinants | Immunoassay Results | | -100% | 0 | N/A | 80 | 80 Negative | | -75% | 2.5 | 2.67 | 80 | 80 Negative | | -50% | 5 | 5.17 | 80 | 80 Negative | | -25% | 7.5 | 7.82 | 80 | 80 Negative | | 100% | 10 | 10.2 | 80 | 42 Negative/ 38 Positive | | +25% | 12.5 | 12.8 | 80 | 80 Positive | | +50% | 15 | 15.2 | 80 | 80 Positive | | +75% | 17.5 | 18.0 | 80 | 80 Positive | | +100% | 20 | 21.5 | 80 | 80 Positive | #### b) Spike Recovery The study was performed for 20 replicates using reagents, calibrators and controls. This study was carried out by testing spiked samples containing 6-Acetylmorphine at the cutoff calibrator and controls levels. The spiked samples were prepared by spiking 6-Acetylmorphine into drug free negative urine. Samples were tested in both Qualitative and Semi-Quantitative mode. The qualitative and semi-quantitative results are summarized in the table below. {7}------------------------------------------------ | Replicate | 7.5 ng/mL (n=20) | 10 ng/mL (n=20) (Rate mA/min) | 12.5 ng/mL (n=20) | |-----------------|---------------------|-------------------------------------|----------------------| | 1 | Negative | 515 | Positive | | 2 | Negative | 513 | Positive | | 3 | Negative | 515 | Positive | | 4 | Negative | 515 | Positive | | 5 | Negative | 516 | Positive | | 6 | Negative | 513 | Positive | | 7 | Negative | 512 | Positive | | 8 | Negative | 519 | Positive | | 9 | Negative | 515 | Positive | | 10 | Negative | 517 | Positive | | 11 | Negative | 517 | Positive | | 12 | Negative | 518 | Positive | | 13 | Negative | 518 | Positive | | 14 | Negative | 517 | Positive | | 15 | Negative | 515 | Positive | | 16 | Negative | 516 | Positive | | 17 | Negative | 520 | Positive | | 18 | Negative | 515 | Positive | | 19 | Negative | 516 | Positive | | 20 | Negative | 518 | Positive | | Overlap | No | No | No | | Relative to C/O | All 20 below C/O | N/A | All 20 above C/O | # c) Analytical Recovery and Linearity Linearity studies were performed in accordance with CLSI Guideline EP06-A. To demonstrate the linearity of the entire assay range, drug free urine was spiked to the high calibrator level (20ng/mL) by using 6-AM methanol solution and diluted with drug free urine to generate 10 intermediate levels. Each sample was run in replicates of five in semi-quantitative mode and the average was used to determine percent recovery compared to the expected target value. The percent recovery is summarized in the table below. | Level | Target Concentration (ng/mL) | Observed Concentration (ng/mL) | Recovery (%) | |-------|------------------------------------|--------------------------------------|--------------| | 1 | 0 | 0.18 | N/A | | 2 | 2 | 2.26 | 113.0 | | 3 | 4 | 4.02 | 100.5 | | 4 | 6 | 6.10 | 101.7 | | 5 | 8 | 7.86 | 98.3 | | 6 | 10 | 9.88 | 98.8 | | 7 | 12 | 11.90 | 99.2 | | 8 | 14 | 13.72 | 98.0 | {8}------------------------------------------------ | 9 | 16 | 15.52 | 97.0 | |----|----|-------|-------| | 10 | 18 | 18.04 | 100.2 | | 11 | 20 | 19.64 | 98.2 | #### d) Method Comparison and Accuracy The method comparison study was performed in accordance with CLSI Guideline EP09-A3. One hundred unaltered patient samples were analyzed by the CEDIA Heroin Metabolite (6-Acetylmorphine) Assay in both qualitative and semi-quantitative modes and the results are compared to LC-MS/MS. The overall concordance between LC-MS/MS and CEDIA Heroin Metabolite (6-Acetylmorphine) Assay is 99%. The qualitative and semi-quantitative results are summarized in the tables below. #### Qualitative Results | Candidate Device Results | Negative | < 50% of Cutoff concentration by LC- MS/MS (<5ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration as determined by LC-MS/MS) (5 – 9.9 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration as determined by LC-MS/MS) (10 – 15.0 ng/mL) | High Positives (Greater than 50% above cutoff concentration (> 15.0 ng/mL) | |--------------------------------|----------|---------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------| | Positive | 0 | 0 | 1* | 5 | 45 | | Negative | 43 | 2 | 4 | 0 | 0 | * Discordant sample Agreement among Positives: 50/50 =100% Agreement among Negative: 49/50=98% #### Semi-Quantitative Results | Candidate Device Results | Negative | < 50% of Cutoff concentration by LC- MS/MS (< 5ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration as determined by LC-MS/MS) (5 - 9.9 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration as determined by LC-MS/MS) (10 - 15.0 ng/mL) | High Positives (Greater than 50% above cutoff concentration (> 15.0 ng/mL) | |--------------------------------|----------|----------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------| | Positive | 0 | 0 | 1* | 5 | 45 | | Negative | 43 | 2 | 4 | 0 | 0 | * Discordant sample Agreement among Positives: 50/50 =100% Agreement among Negative: 49/50=98% {9}------------------------------------------------ #### * Discordant Result Summary | Sample ID | CEDIA 6-AM Urine Assay | | LC-MS/MS (ng/mL) | |--------------|------------------------|------------------------|------------------| | | Qualitative mode | Semi-Quantitative mode | 6-Acetylmorphine | | CA170418-025 | Positive | Positive | 9.61 | Sample showed 13.8 ng/mL in semi-quantitative mode, and is discordant due to cross reactivity to morphine present in the sample at a concentration of 4449 ng/mL as measured by LC-MS/MS #### e) Specificity The cross-reactivity of Heroin Metabolite (6-AM) 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, 6-Acetylmorphine showed 100% cross-reactivity. Heroin showed 6% cross-reactivity. | Heroin Metabolite (6-AM) and its metabolites | Tested Concentration (ng/mL) | Cross- reactivity (%) | |-------------------------------------------------|---------------------------------|-----------------------------| | 6-Acetylmorphine | 10 | 100 | | Heroin | 160 | 6 | #### Cross Reactivity of Structurally Related or Unrelated Opiate Compounds | Opiates and Structurally Related Compounds | Tested Concentration (ng/mL) | Cross- reactivity (%) | |-----------------------------------------------|---------------------------------|--------------------------| | 6-Acetylcodeine | 100,000 | 0.01 | | Buprenorphine | 100,000 | <0.01 | | Buprenorphine-3β-D-glucuronide | 100,000 | <0.01 | | Codeine | 100,000 | <0.01 | | Dextromethorphan | 100,000 | <0.01 | | Dihydrocodeine | 100,000 | <0.01 | | EDDP | 100,000 | <0.01 | | EMDP | 100,000 | <0.01 | | Ethylmorphine | 100,000 | <0.01 | | Fentanyl | 100,000 | <0.01 | | Hydrocodone | 100,000 | <0.01 | | Hydromorphone | 20,000 | 0.05 | | Hydromorphone-3β-D- glucuronide | 100,000 | <0.01 | | LAAM | 100,000 | <0.01 | | Levorphanol | 20,000 | 0.05 | | Methadone | 100,000 | <0.01 | | Meperidine | 100,000 | <0.01 | | Mitragynine | 100,000 | <0.01 | | 7-Hydroxymitragynine | 100,000 | <0.01 | | Morphine | 13,500 | 0.07 | | Morphine-3β-D-Glucuronide | 100,000 | <0.01 | | Morphine-6β-D-Glucuronide | 100,000 | <0.01 | {10}------------------------------------------------ | Nalorphine | 10,500 | 0.10 | |-----------------------------------------------|---------------------------------|--------------------------| | Naloxone | 100,000 | <0.01 | | Naltrexone | 100,000 | <0.01 | | Norbuprenorphine | 100,000 | <0.01 | | Norbuprenorphine glucuronide | 100,000 | <0.01 | | Opiates and Structurally Related Compounds | Tested Concentration (ng/mL) | Cross- reactivity (%) | | Norcodeine | 100,000 | <0.01 | | Norhydrocodone | 100,000 | <0.01 | | Normorphine | 50,000 | 0.02 | | Norpropoxyphene | 100,000 | <0.01 | | Noroxycodone | 100,000 | <0.01 | | Noroxymorphone | 100,000 | <0.01 | | Oxycodone | 100,000 | <0.01 | | Oxymorphone | 100,000 | <0.01 | | Oxymorphone-3β-D-glucuronide | 100,000 | <0.01 | | Tapentadol HCl | 100,000 | <0.01 | | Tramadol | 100,000 | <0.01 | The potential cross-reactivity posed by drugs commonly co-administered with Heroin Metabolite (6-AM) was evaluated by adding each substance to Heroin Metabolite (6-AM) spiked at Low Control, 7.5 ng/mL (-25% of the cutoff concentration) and the High Control, 12.5 ng/mL (+25% of the cutoff concentration) levels at the concentrations indicated. A drug is considered to cross-react if the observed Heroin Metabolite (6-AM) 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. | Structurally Unrelated Compounds Spiked at the Concentration Listed Below | | |---------------------------------------------------------------------------|--| | into Low Control and High Control | | | Structurally Unrelated Compounds | Tested Conc. (ng/mL) | Spiked 6-Acetylmorphine level | | |-------------------------------------|-------------------------|--------------------------------------|---------------------------------------| | | | Low Control Positive/ Negative | High Control Positive/ Negative | | 10,11 Dihydrocarbamazepine | 85,000 | Negative | Positive | | 11-nor-delta9-THC- COOH | 10,000 | Negative | Positive | | Acetaminophen | 500,000 | Negative | Positive | | Acetylsalicylic Acid | 500,000 | Negative | Positive | | Amitriptyline | 125,000 | Negative | Positive | | Amoxicillin | 500,000 | Negative | Positive | | Amphetamine | 100,000 | Negative | Positive | | Amisulpride | 100,000 | Negative | Positive | | Benzotropine Mesylate | 125,000 | Negative | Positive | | Benzoylecgonine | 100,000 | Negative | Positive | | Brompheniramine | 75,000 | Negative | Positive | | Caffeine | 500,000 | Negative | Positive | | Captopril | 500,000 | Negative | Positive | | Chlordiazepoxide | 100,000 | Negative | Positive | | Structurally Unrelated Compounds | Tested Conc. (ng/mL) | Spiked 6-Acetylmorphine level | | | | | Low Control Positive/ Negative | High Control Positive/ Negative | | Chlorpromazine | 10,000 | Negative | Positive | | Clomipramine | 250,000 | Negative | Positive | | Chloroquine | 500,000 | Negative | Positive | | Cimetidine | 500,000 | Negative | Positive | | Desipramine | 125,000 | Negative | Positive | | Diazepam | 100,000 | Negative | Positive | | Digoxin | 100,000 | Negative | Positive | | Diphenhydramine | 50,000 | Negative | Positive | | Doxepine HCl | 50,000 | Negative | Positive | | Enalapril | 500,000 | Negative | Positive | | Fluoxetine | 500,000 | Negative | Positive | | Fluophenazine | 500,000 | Negative | Positive | | Haloperidol | 50,000 | Negative | Positive | | Hydroxychlroquine | 100,000 | Negative | Positive | | Hydroxyzine | 250,000 | Negative | Positive | | Ibuprofen | 500,000 | Negative | Positive | | Imipramine | 50,000 | Negative | Positive | | Levothyroxine | 50,000 | Negative | Positive | | Methamphentamine | 100,000 | Negative | Positive | | Maprotiline | 500,000 | Negative | Positive | | Nalbuphine | 100,000 | Negative | Positive | | Naproxen | 500,000 | Negative | Positive | | Nortryptiline | 250,000 | Negative | Positive | | Nifedipine | 500,000 | Negative | Positive | | Nordiazepam | 100,000 | Negative | Positive | | Oxazepam | 100,000 | Negative | Positive | | Perphenazine | 150,000 | Negative | Positive | | Phencyclidine | 7,500 | Negative | Positive | | Phenobarbital | 100,000 | Negative | Positive | | Procyclidine | 400,000 | Negative | Positive | | Propoxyphene | 25,000 | Negative | Positive | | Protriptyline | 50,000 | Negative | Positive | | Ranitidine | 500,000 | Negative | Positive | | Salicyluric Acid | 500,000 | Negative | Positive | | Secobarbital | 100,000 | Negative | Positive | | Sulpiride | 500,000 | Negative | Positive | | Thioridazine | 250,000 | Negative | Positive | | Triprolidine | 125,000 | Negative | Positive | | Verapamil | 500,000 | Negative | Positive | {11}------------------------------------------------ {12}------------------------------------------------ ## f) The interference studies were performed in accordance with CLSI Guideline EP07-A2. The potential interference of pH and endogenous physiologic substances on recovery of 6-AM using CEDIA Heroin Metabolite (6-AM) Urine Assay was assessed by spiking known compounds of potentially interfering substances into the Low Control, 7.5 ng/mL (-25% of the cutoff concentration) and the High Control, 12.5 ng/mL (+25% of the cutoff concentration). In the presence of the compounds listed below, the controls were detected accurately, indicating that these compounds did not show interference in the assay. | Compound | Tested Concentration (mg/dL) | Spiked 6-Acetylmorphine level | | |---------------------|------------------------------------|----------------------------------------------|---------------------------------------------| | | | Low Control -25% of cutoff (7.5 ng/mL) | High Control +25% cutoff (12.5 ng/mL) | | Acetone | 1000 | Negative | Positive | | Ascorbic acid | 1500 | Negative | Positive | | Creatinine | 500 | Negative | Positive | | Ethanol | 1000 | Negative | Positive | | Galactose | 10 | Negative | Positive | | Y-globulin | 500 | Negative | Positive | | Glucose | 1000 | Negative | Positive | | Hemoglobin | 300 | Negative | Positive | | Human serum albumin | 500 | Negative | Positive | | Oxalic acid | 100 | Negative | Positive | | Riboflavin | 7.5 | Negative | Positive | | Sodium Chloride | 6000 | Negative | Positive | | Urea | 2000 | 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 | Negative | * pH 11 urine interferes CEDIA 6-AM urine assay. #### Specific Gravity Drug free urine samples with specific gravity ranging in value within 1.002 to 1.030 were split and spiked to a final concentration of either 7.5 ng/mL or 12.5 ng/mL (the {13}------------------------------------------------ Low Control and High Control concentrations, respectively). These samples were then evaluated in both qualitative and semi-quantitative modes. No interference was observed. | Specific Gravity | Spiked 6-Acetylmorphine Concentration | | |------------------|---------------------------------------|--------------| | | Low Control | High Control | | 1.004 | Negative | Positive | | 1.005 | Negative | Positive | | 1.007 | Negative | Positive | | 1.010 | Negative | Positive | | 1.011 | Negative | Positive | | 1.013 | Negative | Positive | | 1.019 | Negative | Positive | | 1.023 | Negative | Positive | | 1.025 | Negative | Positive | | 1.029 | Negative | Positive | # g) Clinical cutoff SAMHSA guideline for 6-Acetylmorphine is 10 ng/mL cutoff. #### H. Conclusion The information supports a determination of substantial equivalence between CEDIA Heroin Metabolite (6-AM) Assay and the predicate device CEDIA DAU 6-Acetylmorphine Assay (k001178).