(258 days)
The Psychemedics Microplate EIA For Fentanyl in Hair is an in vitro diagnostic device for the qualitative detection of fentanyl in hair. The assay is intended for use in workplace settings for the qualitative analysis of human head and body hair. The assay uses a cutoff calibrator of 0.2 ng fentanyl/10 mg hair.
Psychemedics plans to perform this test at one site. Psychemedics has not performed an evaluation of reproducibility at different laboratories.
The Psychemedics Microplate EIA For Fentanyl in Hair provides only a preliminary analytical test result. A more specific alternate chemical method must be used to obtain a confirmed analytical result. Liquid Chromatography/Mass spectrometry/Mass spectrometry (LC/MS/MS) using deuterated internal standards in multiple reaction monitoring (MRM) mode is the confirmatory method used by Psychemedics Corporation. This confirmatory method uses a cutoff of 0.2 ng of fentanyl/10 mg hair.
The Psychemedics Microplate EIA For Fentanyl in Hair consists of two parts; a pre-analytical hair treatment procedure (to convert the solid matrix of hair to a measurable liquid matrix) and the screening assay, the Psychemedics Microplate EIA for Fentanyl. The screening portion of the test system consists of (1) microplate wells coated with fentanyl conjugated to bovine serum albumin (BSA), monoclonal rabbit anti-fentanyl, goat anti-rabbit secondary antibody conjugated to HRP (horseradish peroxidase), substrate [3, 3', 5, 5' tetramethylbenzidine (TMB)], HCl to acidify (and stop the reaction), and wash buffer for washing the plates. Absorbance in the wells is read with a microplate reader.
Here's a breakdown of the acceptance criteria and the supporting study for the Psychemedics Microplate EIA for Fentanyl in Hair device:
Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Criteria | Reported Device Performance |
|---|---|---|
| Precision | Intra-Assay and Inter-Assay Precision around cutoff | Intra-Assay Precision:- B₀ (-100%): 10 negative, 0 positive- -75%: 10 negative, 0 positive- -50%: 10 negative, 0 positive- -25%: 10 negative, 0 positive- Plus 25%: 0 negative, 10 positive- Plus 50%: 0 negative, 10 positive- Plus 75%: 0 negative, 10 positive- Plus 100%: 0 negative, 10 positiveInter-Assay Precision:- B₀ (-100%): 50 negative, 0 positive- -75%: 50 negative, 0 positive- -50%: 50 negative, 0 positive- -25%: 50 negative, 0 positive- Plus 25%: 0 negative, 50 positive- Plus 50%: 0 negative, 50 positive- Plus 75%: 0 negative, 50 positive- Plus 100%: 0 negative, 50 positive |
| Comparison Testing | No False Negatives relative to LC/MS/MS | No false negative EIA results occurred relative to LC/MS/MS. |
| Limited False Positives relative to LC/MS/MS at cutoff. | Ten positive EIA results did not confirm at or above the 0.2 ng fentanyl/10 mg hair cutoff by LC/MS/MS due to washing effects or cross-reactivity with other fentanyl compounds. | |
| Cross-Reactivity | Expected cross-reactivity for related compounds, no cross-reactivity for unrelated compounds. | - Fentanyl and several analogs (Butyryl, Valeryl, Furanyl, Acetyl, o-Fluorofentanyl, Acryl, Cyclopropyl, Isobutyryl, Ocfentanil, 4-Fluoro-isobutyryl) showed high cross-reactivity (100% to 200%).- Other related compounds show lower cross-reactivity (e.g., (+/-)-cis-3-methylfentanyl at 9.1%, Methyl fentanyl at 2%).- Many unrelated compounds (e.g., stimulants, opiates, benzodiazepines, cannabinoids, etc.) showed no cross-reactivity. |
| Interference | No significant interference from commonly found substances. | A wide range of specified compounds (e.g., amoxicillin, caffeine, ibuprofen, naproxen, various illicit drugs like cocaine, heroin metabolites) and mixes showed no interference in the Fentanyl EIA assay. |
| Cosmetic Treatments | EIA results for negative and positive samples are unaffected by cosmetic treatments (bleach, perm, dye, relaxer, shampoo). | - Negative hair samples remained negative after bleach, permanent wave, dye, relaxer, and shampoo treatments.- For positive samples, fentanyl concentration change ranged from 98.4% (shampoo) to 106.5% (relaxer) of untreated samples for dye, relaxer, shampoo, and perm, indicating no significant loss or false positivity. |
| Environmental Contamination | Environmental contamination does not lead to false positives above cutoff after washing procedure. | After an extensive washing procedure, samples contaminated with 2 ng fentanyl/mL of saline resulted in concentrations from below LOQ to 0.0527 ng/10 mg hair, which is well below the 0.2 ng/10 mg hair cutoff. |
| Sample Stability | Fentanyl in hair samples remains stable during shipping and storage. | Five samples showed no significant differences between results before and after shipping and one month of storage. |
| Recovery (EIA) | Sufficient recovery of fentanyl after hair digestion. | Recovery of fentanyl in the digestion method was shown to be at least 80% complete at 2 hours. |
| Recovery (LC/MS/MS) | High recovery of fentanyl and norfentanyl from hair. | Recovery of fentanyl and norfentanyl from 5 authentic samples was greater than 96%. Recoveries of analytes and internal standards with SPE were greater than 50% with <5% CV precision. Averages of 5 samples were 98 - 102% of target concentrations. |
| LC/MS/MS Precision (around cutoff and over range) | Acceptable precision for LC/MS/MS results. | All sets of replicates had < 10% CV. Averages of all replicates were within 15% of target concentration. |
| LC/MS/MS Linearity | Linearity across the assay range. | Demonstrated from 0.01 to 7.5 ng/10 mg hair. All results were within 15% of target concentrations. Agreement of 5 determinations at each concentration was < 10% CV. Regression coefficient > 0.995. Actual data points deviated < 10% from regression line. |
| Validity of Dilution (LC/MS/MS) | Accurate results upon dilution. | Agreement of 5 determinations was < 10% CV. Averages of 5 determinations at each dilution were within 15% of target values. |
| Carryover (LC/MS/MS) | No carryover at the upper limit of linearity (ULOL). | No signal was detected in negative samples following 7.5 ng/10 mg hair samples, indicating no carryover up to 7.5 ng/10 mg hair. |
| Matrix Effects (LC/MS/MS) | No significant ion suppression or enhancement. | No ionization suppression or enhancement greater than +/- 15% was observed. |
| Interference from Internal Standard/Analytes (LC/MS/MS) | No cross-contamination between deuterated and non-deuterated compounds. | No peaks detected in the D5 window for samples without internal standard (D3), and no peaks detected in the D0 window for samples without analytes. |
| Interference from other compounds (LC/MS/MS) | No interference from a broad panel of other compounds. | No interference detected from 37 individual compounds and 38 compounds in 5 mixes. |
| Accuracy (LC/MS/MS) | Accurate measurements demonstrated through proficiency testing and statistical analysis. | Proficiency testing samples were near target concentrations and within the range of other participating labs. Linearity and precision data support accuracy (averages within 15% of target). LLOQ determined at 0.01 ng/10 mg hair with adequate S:N ratios. Reproducibility across multiple hair types showed >90% of target and <10% CV. |
Study Information: Psychemedics Microplate EIA for Fentanyl in Hair
-
Sample size used for the test set and the data provenance:
- Test Set Sample Size: 197 samples (comprising both head and body hair) were used for comparison testing against the confirmatory method.
- Data Provenance: Not explicitly stated regarding country of origin. The study appears to be retrospective, using collected hair samples.
-
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This is a laboratory diagnostic device that performs an analytical test. The ground truth is established by a more specific alternative chemical method, not by human expert interpretation.
- The "ground truth" for the test set was established by Liquid Chromatography/Mass spectrometry/Mass spectrometry (LC/MS/MS), which is the confirmatory method. Clinical laboratory personnel perform these tests, not "experts" in the sense of physicians interpreting images.
-
Adjudication method for the test set:
- Not applicable in the traditional sense of human adjudication for classification tasks. The adjudication is done by comparing the screening EIA results to the LC/MS/MS confirmatory results. Any discrepancies (e.g., EIA positive, LC/MS/MS negative) are analyzed for root cause (e.g., washing effects, cross-reactivity).
-
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, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is a diagnostic assay (EIA followed by LC/MS/MS), not an AI-assisted diagnostic tool that requires human interpretation.
-
If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- Yes, the performance presented for the Psychemedics Microplate EIA for Fentanyl in Hair is entirely standalone (algorithm/assay only). The EIA provides a preliminary analytical test result without human interpretation of the assay itself being a variable. The human "in-the-loop" would be the laboratory technician performing the assay and subsequently the LC/MS/MS confirmation, but the performance metrics are for the assay's ability to accurately detect fentanyl.
-
The type of ground truth used:
- The primary ground truth for the comparison study was Liquid Chromatography/Mass spectrometry/Mass spectrometry (LC/MS/MS) results. This is considered the definitive analytical method for confirming the presence and concentration of fentanyl in hair samples.
-
The sample size for the training set:
- This is a traditional diagnostic assay, not a machine learning model. Therefore, there isn't a "training set" in the context of an AI/ML algorithm. The performance testing involves samples used for validation, but not in the sense of training a model.
- Calibrators and controls: The calibrators and control materials are prepared from commercially purchased stocks, and their concentrations are confirmed by LC/MS/MS. These are established analytical standards, not a training set for an algorithm.
-
How the ground truth for the training set was established:
- As this is not an AI/ML device, the concept of a "training set ground truth" does not apply. The calibrators and controls' "ground truth" (i.e., their known concentrations) are established by highly accurate methods like LC/MS/MS using specific certificates of analysis for the drug stocks.
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SUMMARY (K182103)
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the
requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K182103
| Submitted By: | Psychemedics Corporation5832 Uplander WayCulver City, CA 90230TEL: 310 216 7776FAX: 310 216 6662 |
|---|---|
| Submission Contact: | Virginia Hill |
| Date Prepared: | August 2, 2018 |
| Device Trade Name: | Psychemedics Microplate EIA for Fentanyl in Hair |
| Predicate Device: | Psychemedics Microplate EIA for Opiates in Hair |
| Product Code: | DJG |
| Device Classification/Name: | 21 CFR 862.3650, Opiate Test System;Classification II; |
| Intended Use: | The Psychemedics Microplate EIA For Fentanyl in Hair is an in vitrodiagnostic device for the qualitative detection of fentanyl in hair. Theassay is intended for use in workplace settings for the qualitativeanalysis of human head and body hair. The assay uses a cutoffcalibrator of 0.2 ng fentanyl/10 mg hair.Psychemedics plans to perform this test at one site. Psychemedics hasnot performed an evaluation of reproducibility at different laboratories.The Psychemedics Microplate EIA For Fentanyl in Hair provides onlya preliminary analytical test result. A more specific alternate chemicalmethod must be used to obtain a confirmed analytical result. LiquidChromatography/Mass spectrometry/Mass spectrometry (LC/MS/MS)using deuterated internal standards in multiple reaction monitoring(MRM) mode is the confirmatory method used by PsychemedicsCorporation. This confirmatory method uses a cutoff of 0.2 ng offentanyl/10 mg hair. |
| Limitations: | The assay is designed only for human body and head hair.The results of the Psychemedics Microplate EIA For Fentanyl in Hairshould be used solely for workplace decisions—to make hiring andemployment decisions. The results of the test should not be used to makedecisions to initiate, change, or stop medical or mental health therapy |
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Positive screening results only indicate the presumptive presence of fentanyl and require additional analysis by mass spectrometry to obtain a confirmed result. Certain medication or dietary supplements that contain fentanyl and/or compounds that may be metabolized to produce fentanyl may cause a positive result. Studies to determine the correlation of the typical doses for those drugs and dietary supplements to concentrations of fentanyl in hair have not been performed. The clinical performance of this assay has not been characterized with regard to the amount and frequency of fentanyl ingestion needed to test positive. Negative results should be interpreted with caution.
A negative screening test result does not necessarily rule out the possibility of fentanyl use, i.e., time of collection, frequency of use, mode of ingestion, dosage used, hair types and other factors may influence results. It is not possible to document all possible effects due to treatments such as bleaching, straightening and dyeing. There is a possibility that other substances and/or factors not listed above may interfere with the test and cause false results that cannot be confirmed by mass spectrometry.
The assay is designed only for human body and head hair.
The results of the Psychemedics Microplate EIA For Fentanyl in Hair should be used solely for workplace decisions-to make hiring and employment decisions. The results of the test should not be used to make decisions to initiate, change, or stop medical or mental health therapy
Positive screening results only indicate the presumptive presence of fentanyl and require additional analysis by mass spectrometry to obtain a confirmed result. Certain medication or dietary supplements that contain fentanyl and/or compounds that may be metabolized to produce fentanyl may cause a positive result. Studies to determine the correlation of the typical doses for those drugs and dietary supplements to concentrations of fentanyl in hair have not been performed. The clinical performance of this assay has not been characterized with regard to the amount and frequency of fentanyl ingestion needed to test positive. Negative results should be interpreted with caution.
A negative screening test result does not necessarily rule out the possibility of fentanyl use, i.e., time of collection, frequency of use, mode of ingestion, dosage used, hair types and other factors may influence results. It is not possible to document all possible effects due to treatments such as bleaching, straightening and dyeing. There is a possibility that other substances and/or factors not listed above may interfere with the test and cause false results that cannot be confirmed by mass spectrometry.
Assay Description: The Psychemedics Microplate EIA For Fentanyl in Hair consists of two parts; a pre-analytical hair treatment procedure (to convert the solid matrix of hair to a measurable liquid matrix) and the screening assay, the Psychemedics Microplate EIA for Fentanyl. The screening portion of the test system consists of (1) microplate wells coated with fentanyl conjugated to bovine serum albumin (BSA), monoclonal rabbit anti-fentanyl, goat anti-rabbit
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secondary antibody conjugated to HRP (horseradish peroxidase), substrate [3, 3', 5, 5' tetramethylbenzidine (TMB)], HCl to acidify (and stop the reaction), and wash buffer for washing the plates. Absorbance in the wells is read with a microplate reader.
Sample Collection & Stability:
A sample of hair should be cut as close as possible to the skin. The hair is placed in a V-shaped aluminum foil sample holder with the root end of the hair protruding beyond the slanted edge of the foil. The aluminum foil is crimped around the sample, securing the hair specimen firmly into place within the foil. The hair sample, crimped within the foil, is placed in a sample acquisition card envelope and the envelope is sealed with a tamper-evident seal. Hair specimens are kept at ambient temperature in a secure location until they are shipped without refrigeration to the laboratory. Stability of fentanyl in hair samples stored at room temperature has been shown for over one month. Fentanyl in samples shipped coast-to-coast twice was stable.
| Materials required: | Hair sample collection kit, Microplate for Fentanyl, Microplate washer and reader, LC/MS/MS for confirmation. |
|---|---|
| --------------------- | --------------------------------------------------------------------------------------------------------------- |
| Item | Proposed Device | Opiates in Hair Assay |
|---|---|---|
| Indications/Intended use | The Psychemedics Microplate EIAfor Fentanyl in hair is an enzymeimmunoassay (EIA) for thepreliminary qualitative detection offentanyl in human head and bodyhair using a fentanyl calibrator at0.2 ng /10 mg hair cutoff foridentifying fentanyl use.The Psychemedics Microplate EIAFentanyl assay provides only apreliminary analytical test result. Amore specific alternative chemicalmethod must be used in order toobtain a confirmed analyticalresult. Liquid Chromatographywith MS/MS is the preferredconfirmatory method. | The Psychemedics Microplate EIAfor Opiates in Hair (K111926) is aqualitative kit for detection ofopioids in hair. This assay providesonly a preliminary analytical testresult. A more specific alternativechemical method must be used inorder to obtain a confirmedanalytical result. LiquidChromatography with MS/MS is thepreferred confirmatory method. |
| Product Code | DJG | DJG |
| Measurand | Fentanyl in Hair | Opioids |
| Test System | Psychemedics Microplate EIA forFentanyl in Hair | Psychemedics EIA for opiates inHair |
| Sample Matrix | Human Hair | Human hair |
| Method of Measurement | Microplate reader, read at 450 nm | Microplate reader, read at 450 nm |
| Cutoff | 0.2 ng fentanyl/10 mg hair | 2 ng morphine/10 mg hair |
| Type of Test | Enzyme Immunoassay | Enzyme Immunoassay |
| Extraction Method | Patented Digestion method | Patented Digestion method |
| Confirmation Method | LC/MS/MS | LC/MS/MS |
Comparison with Predicate:
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Summary of Performance Testing of the EIA
The precision studies were performed by spiking negative hair with previously LC/MS/MS-validated calibrator and control spiking solutions to achieve concentrations of negative, the cutoff of 0.2 ng/10 mg hair, and +/-75%, +/-50%, and +/- 25% of the cutoff. Precision Studies
| Summary -Intra-Assay | Summary-Inter-Assay | ||||
|---|---|---|---|---|---|
| LEVEL | NEG | POS | LEVEL | NEG | POS |
| B₀ (-100%) | 10 | 0 | B₀ (-100%) | 50 | 0 |
| -75% | 10 | 0 | -75% | 50 | 0 |
| -50% | 10 | 0 | -50% | 50 | 0 |
| -25% | 10 | 0 | -25% | 50 | 0 |
| plus 25% | 0 | 10 | plus 25% | 0 | 50 |
| plus 50% | 0 | 10 | plus 50% | 0 | 50 |
| plus 75% | 0 | 10 | plus 75% | 0 | 50 |
| plus 100% | 0 | 10 | plus 100% | 0 | 50 |
ComparisonTesting
197 samples comprising both head and body hair were confirmed by LC/MS/MS in parallel with testing by the Psychemedics Fentanyl EIA. Relative to the LC/MS/MS results, no false negative EIA results occurred. Ten positive EIA results did not confirm at or above the cutoff of 0.2 ng fentanyl/10 mg hair by LC/MS/MS; these false positives were due to effects of washing before confirmation or to crossreactivity with other fentanyl compounds.
Conclusions:
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- No samples that screened negative were false negatives-i.e., no sample that screened negative confirmed above 0.2 ng/10 mg hair of any fentanyl.
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- The comparison studies demonstrate substantial equivalence between the performance of the screening device and the LCMSMS confirmation. Cutoffs are appropriately set such that positivity of the EIA predicts positivity at > 0.2 ng/10 mg hair by LCMSMS.
Cosmetic Treatments
Twenty fentanyl-negative head hair samples were treated with bleach, 20 with permanent wave, 20 with dye (which includes bleach), 20 with relaxer, and 20 with shampoo, and the results compared to the same samples without the treatments. In each case of the 20 samples treated with a type of cosmetic treatment, 10 samples were treated with one brand of a particular product and 10 other samples with a second brand. No significant differences in EIA results were observed for the negative hair samples before and after the treatments; all samples remained negative after the treatments.
Twelve fentanyl-positive head hair samples were treated with permanent wave, dye, relaxer, or shampoo, and the results compared to the same samples without the treatments. In each case of samples treated with a type of cosmetic treatment, 6 samples were treated with one brand of a particular product and 6 with a second brand.
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| TREATMENT | (Fentanyl in Treated Samples / Fentanylin Untreated Samples) X 100 |
|---|---|
| Dye (with bleach) | 106.3 |
| Relaxer | 106.5 |
| Shampoo | 98.4 |
| Perm | 101 |
Summary of Cross-reactivity and Interference Studies
Cross-reactivity of Related Compounds in Fentanyl EIA
| Percent Cross-reactivity* | Expected Concentration Equivalentto 0.2 ng Fentanyl/10 mg hair | |
|---|---|---|
| Compound | ||
| Fentanyl | 100 | 0.20 |
| Butyryl fentanyl | 200 | 0.10 |
| Valeryl fentanyl | 100 | 0.20 |
| Furanyl fentanyl | 100 | 0.20 |
| Acetyl fentanyl | 125 | 0.16 |
| o-Fluorofentanyl | 100 | 0.20 |
| Acryl Fentanyl | 100 | 0.20 |
| Cyclopropyl fentanyl | 100 | 0.20 |
| Isobutyryl fentanyl | 100 | 0.20 |
| Ocfentanil | 100 | 0.20 |
| 4-Fluoro-isobutyryl fentanyl | 100 | 0.20 |
| Acetyl fentanyl | 125 | 0.16 |
| (+/-)-cis-3-methylfentanyl | 9.1 | 2.2 |
| Methyl fentanyl | 2 | 10.0 |
| Despropionyl fentanyl | 0.7 | 29.0 |
| Sufentanil citrate | < 0.2 | N/A |
| Remifentanil | < 0.2 | N/A |
| Alfentanil | < 0.2 | N/A |
| Norfentanil | < 0.2 | N/A |
| Benzylfentanil | < 0.2 | N/A |
| Acetylnorfentanil oxalate | < 0.2 | N/A |
| Carfentanil Oxalate | < 0.2 | N/A |
The following compounds were shown to have no cross-reactivity in the Fentanyl EIA assay:
Anhydroecgonine methyl ester, Ethosuximide, Naproxen, Atropine, Haloperidol, Nicotine, Bupropion, Ibuprofen, Nortriptyline, Cotinine, LSD , Propoxyphene, Cannabinol, Meperidine, R.R Pseudoephedrine, Chlorpheniramine maleate, Methadone, Thioridazine, O-Desmethyvenlafaxine, Methaqualone, Cis-Tramadol, Despiramine, Methyl phenidate, Venlafaxine hydrochloride, Doxylamine succinate, Naloxone, 8(-)-11-nor-9-Carboxy-delta9 THC, 1S, 2R Ephedrine, Naltrexone, 11-nor-9-Carboxy-delta9-THC, Amoxicillin, Ethylmorphine, Cocaethylene, Propanolol, Nalorphine, Cocaine, Promethazine, Phenmetrazine, Morphine, Phendimetrazine, Hydromorphone, Benzocaine, Oxycodone, Ecgonine, Benzoylecgonine, Methamphetamine (+/-), epinephrine (+/-), metanephrine (+/-), vanilmandelic acid(+/-), methadone (+/-), acetaminophen, Cocaethylene, Cocaine, norepinephrine (+/-), normetanephrine (+/-), 5-hydroxyindole-3-acetic acid, codeine, caffeine, Cocaine, Heroin, homovanillic acid, hydrocodone, chlorphenirame maleate, Ecgonine Methyl Ester, meperidine, oxycodone, CP 47, 497 (+/-), AM2201, CP 47, 497 (+/-), C8 homologue, JWH-019, HU-211, JWH-081, JWH-200, JWH-122, JWH-250, Glutethimide, Flurazepam, Carbamazepine, Acetaminophen, Amitriptyline, Meprobamate, Lorazepam, Diazepam, Caffeine, Dextromethorphan, Methyprylon, Medazepam, Dyphylline, Imipramine, Lidocaine, Temazepam, Oxazepam, Methamphetamine, Methocarbamol,
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Theophylline, Phencyclidine, Nordoxepin, Phenmetrazine, Phenylpropanolamine, Phenylephrine, Triamterene, ethosuximide, a-methyl-a-propylsuccimide, methsuximide, phensuximide, N-Normethsuximide, Mephenytoin, Ethotoin, Mephobarbital, PEMA, Phenobarbital, Methyl PEMA, 10,11-Dihydrocarbamazepine, Primidone, Carbamazepine, 5,5-Diphenylhydantoin, 4-Methylprimidone, Butabarbital, Medazepam, Amitriptyline, Glutethimide, Amobarbital, Desipramine, Methaqualone, Secobarbital, Lorazopam, Doxepin, Diazepam, Hexobarbital, Diazepam, Imipramine, Phenobarbital, Temazepam, Nordoxepin, Flurazepam, Bromazepam, Norrtiptyline, Protriptyline, Trimipramine.
Interference
The following compounds were shown to have no interference in the Fentany] EIA assay.
Anhydroecgonine methyl ester, Atropine, Bupropion, Cotinine, Cannabinol, Chlorpheniramine maleate, O-Desmethylyenlafaxine. Desipramine succinate. 1S. 2R Ephedrine. Ethosuximide. Haloperidol. buprofen, LSD, Meperidine, Methyl phenidate, Naloxone, Naltrexone, Naproxen, Nicotine, Nortriptyline, Propoxyphene, R,R Pseudoephedrine, Cis-Tramadol, Venlafaxine hydrochloride, 8(-)-11-nor-9-Carboxy-delta-9-THC, 11-nor-9-Carboxy-delta-9-THC Delta8TH, C Streptomycin solution, Procaine, Benzocaine, Erythromycin, Penicillin G, Mepivacaine, Phendimetrazine bitartrate, Diazepam, Despropionyl, fentanyl, Amoxicillin, Propanolol, Prometrazine, Phendimetrazine, Ecgonine, Metanephrin, Cocaethylene, Cocaine, Glutethimide, Meprobamate, Methyprylon, Acetaminophen, Caffeine, Amitriptyline, Dextromethorphan, Lidocaine, Methocarbamol, Nordoxepin, Phenylephrine, Triamterene, a-methyl-apropylsuccimide, metharbital, methsuximide, phensuximide, N-Normethsuximide, Mephenytoin, Ethotoin, Mephobarbital, PEMA, Phenobarbital, Methyl PEMA, 10,11-Dihydrocarbamazepine, Primidone, Carbamazepine, 5.5-Diphenylhydantoin, 4-Methylprimidone, Chlorpromazine, Dyphylline, Methaqualone, Theophylline, Imipramine, Phenmetrazine, Triamterene, Ethylmorphine, Nalorphine, Codeine, Morphine, Hydromorphone, Oxycodone, Metanephrine (+/-), Normetanephrine (+/-), Vanilmandelic acid(+/-), 5-Hydroxyindole-3-acetic acid, Homovanillic acid, R,R(-)-Pseudoephedrine, Buprenorphine, Codeine, Hydrocodone, Meperidine, Morphine, Oxymorphone, Spice CP 47, Spice C8 homologue, Spice HU-211, Spice JWH-200, Spice JWH-250, Spice CP 497 (+/-),Spice AM2201, Spice JWH-019, Spice JWH-081, Spice JWH-122
Calibrator
Psychemedics prepares calibrators and control materials using stocks purchased from a commercial vendor. Each lot of drug is received with its specific certificate of analysis. The commercially obtained stock is made into the calibrators and controls to the desired concentrations. The concentrations are confirmed by LC/MS/MS.
Sample Stability During Shipping and Storage
Five samples showed no significant differences between results before and after shipping and one month of storage.
Recovery
The hair sample preparation for the screening assay is by a nonproteolytic digestion procedure (US Patent 8,084,215) carried out at 37°C. Recovery of fentanyl in the method was shown to be at least 80% complete at 2 hours.
Environmental Contamination
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Potential environmental contamination of samples that are identified as presumptive positive in the screening assay is addressed by an extensive washing procedure prior to confirmation. Drug from environmental contamination or deposited by sweat is also removed by the wash procedure.
After washing by the procedure described below, 9 different samples of hair contaminated by soaking in 2 ng fentanyl/mL of saline resulted in amounts of drug from below LOQ to 0.0527 ng of fentanyl /10 mg hair, well below the cutoff of 0.20 ng/10 mg hair.
The Aqueous Buffer Wash Procedure
- a. Wash by Psychemedics' standard wash procedure:
- Add 2 mL of dry isopropanol and shake in waterbath for 15 minutes at 37℃ with shaking @ i. 100 -120 oscillations/minute. Remove isopropanol.
- ii. Add 2 mL of Wash Buffer (0.01 M phosphate buffer, pH 6.0, containing 0.1% BSA) and shake in waterbath for 30 minutes at 37°C with shaking @ 100 -120 oscillations/minute. Remove Buffer.
- iii. Repeat Step ii. two more times.
Summary of Performance Testing of the LCMSMS for Fentanyl and Norfentanyl in Hair
Recovery
Recovery from Hair
Recovery of fentanyl and norfentanyl from hair. tested with 5 authentic samples, was greater than 96%.
Recovery of Analytes and Internal Standard with SPE
Comparison of (1) analysis of analytes and Internal Standards directly without extraction of matrix BEFORE addition of analytes and internal standards) with (2) analysis of analytes and Internal Standards extracted from matrix was carried out. Recoveries of analytes and I.S. were greater than 50%, and precisions were less than 5% CV. Averages of 5 samples were 98 - 102% of target concentrations.
Precision
Intra-Assay Precision Around the Cutoff
Precision of 5 analyses of concentrations around the cutoff was evaluated at 0.1, 0.15, 0.2, 0.25, 0.3 ng/10 mg hair.
Intra-Assay Precision over the Range of the Assay
The concentrations evaluated were 5 samples each of 0.01, 0.02, 0.04, 0.06, 0.08, 0.1, 0.15, 0.2, 0.25,
1.5,
4.5, 6.0, 7.5 ng/10 mg hair.
Intra-Assay Precision Around the Cutoff
The concentrations evaluated were 5 samples each, for 5 days, of 0.1, 0.2, 0.3 ng/10 mg hair
Results:
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All sets of replicates had < 10% CV. Averages of all replicates were within 15% of target concentration.
Linearitv
Linearity was tested by analyzing 5 samples each of fentanyl at the following concentrations: 0.01, 0.02, 0.04, 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 1.5, 4.5, 6.0, 7.5 ng/10mg.
The following results of the study are true for both analytes. All results were within 15 percent of target concentrations. Agreement of 5 determinations at each concentration was < 10% CV. The regression coefficient was > 0.995. The average value of 5 determinations was within 15% of the predicted Y value. The actual data points deviated less than 10% from the regression line. Linearity of the Fentanyl/Norfentanyl Assays from 0.01 to 7.5 ng/10 mg hair was demonstrated.
Validity of Dilution was demonstrated by analyzing 3 dilutions of a 3 ng/100 uL solution of fentanyl and norfentanyl, resulting in 1.25, 0.25 and 0.125 ng/10 mg hair. Agreement of 5 determinations were < 10% CV. The averages of 5 determinations at each dilution was within 15% of the target values.
Carryover
The ULOL was set at 7.5 ng/10 mg hair in the linearity study. Carryover from this highest point of the assay range was tested by preparing 5 tubes at 7.5 ng/10 mg hair and analyzing them with a negative sample following each of the five 7.5 ng/10 mg hair samples. No signal was detected in the negative samples, indicating tht up to 7.5 ng/10 mg hair, carryover is not a factor. Sample greater than 7.5 ng/10 mg hair may require repeating.
Specificity
Matrix Effects
Ion Suppression|Enhancement. Comparison was made of (1) analysis of neat analytes and deuterated internal standard, with (2) analysis of analytes added to eluent of extracted negative matrix. This exercise identifies whether components of the matrix are present in the final eluent that may cause ion suppression or enhancement. No ionization suppression or enhancement greater than +/- 15% was observed.
Interference from Internal Standard or nondeuterated analytes. Samples containing no internal standard (D3) did not show presence of any peaks in the Ds window, showing that there is no D5 contaminant in the Dg analytes. Samples containing no analytes did not show presence of any peaks in the Do window, showing that there is no Do contaminant in the D5 analytes.
Interference from other compounds. Thirty seven individual compounds and 38 compounds in 5 mixes were tested for interference in the LCMSMS assay. No interference was detected.
Accuracy
Results of 5 different proficiency testing samples obtained quarterly from Arvecon (Arvecon GmBH, Kleinfeldweg 52, 69190 Walldorf, Germany) were near the target concentrations in the surveys, and near the center of the ranges obtained by all participating laboratories in these surveys.
Linearity and Precision Data (see above) Support Accuracy. The average values of all replicate determinations were within 15% of the predicted Y value and the target concentrations.
LLOO Precision. LLOO was determined to be at 0.01 ng/10 mg hair. LOD was administratively also set at that level. Signal-to-noise ratios for 5 samples spiked at 0.01 ng/10 mg hair were 382 - 717 for fentanyl and 47 to 78,
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both much greater than the required 19:1 to 20:1 S:N recomment C62-A. Results showed 95.4% and 89.4% of target, respectively for fentanyl and norfentanyl.
Specificity Data. Accuracy is supported by the specificity results in that (1) no ion suppression/enhancement was demonstrated;(2) no traces of deuterated analyte in the nondeuterated analytes, and no nondeuterated analyte in the deuterated analytes was found; and (3) no interference from 37 individual compounds and 5 mixes was found.
Absence of Carryover up to ULOL ensures accuracy of low concentration results.
Averages of agreement among triplicate analyses of 4 authentic positive hair samples showed less than 15% CV.
Reproducibility among samples of multiple hair types spiked at LLOO/LOD, Cutoff, mid-range of assay showed >90% of target concentrations and <10% CV precision.
Conclusion:
The Psychemedics Microplate EIA for Fentanyl in Hair is substantially equivalent based on acceptable performance studies, including precificity, interference (including cosmetic effects), and removal of external contamination.
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Image /page/10/Picture/0 description: The image contains the logos of the U.S. Department of Health & Human Services and the U.S. Food & Drug Administration (FDA). The Department of Health & Human Services logo is on the left, and the FDA logo is on the right. The FDA logo is a blue square with the letters "FDA" in white, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue. The logos are placed side-by-side.
April 18, 2019
Psychemedics Corporation Virginia Hill Vice-President, Research and Development 5832 Uplander Way Culver City, CA 90230
Re: K182103
Trade/Device Name: Psychemedics Microplate EIA for Fentanyl in Hair Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate test system Regulatory Class: Class II Product Code: DJG Dated: March 15, 2019 Received: March 18, 2019
Dear Virginia Hill:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.
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,
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
§ 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).