(151 days)
In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems.
A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.
The ONLINE TDM Vancomycin Gen.3 is a two reagent assay for the in vitro quantitative determination of vancomycin in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles in solution (KIMS). A competitive reaction takes place between the drug conjugate and vancomycin in the serum sample for binding to the vancomycin antibody on the microparticles. The resulting kinetic interaction of microparticles is indirectly proportional to the amount of drug present in the sample.
The provided text details the performance evaluation of the "ONLINE TDM Vancomycin Gen.3" device. Here's a breakdown of the requested information:
1. A table of acceptance criteria and the reported device performance
The document doesn't explicitly state "acceptance criteria" as separate rows but presents performance study results, implying these results are considered acceptable for substantial equivalence. The table below compiles the reported performance data.
| Performance Metric | Acceptance Criteria (Implied by reported performance) | Reported Device Performance (ONLINE TDM Vancomycin Gen.3) |
|---|---|---|
| Detection Limit | ||
| Limit of Blank (LoB) | $\le$ 1.0 µg/mL | MP Lot: 0.6 µg/mL P2 Lot: 0.7 µg/mL P3 Lot: 0.5 µg/mL |
| Limit of Detection (LoD) | $\le$ 1.5 µg/mL | MP Lot: 1.4 µg/mL P2 Lot: 1.3 µg/mL P3 Lot: 1.1 µg/mL |
| Limit of Quantitation (LoQ) | $\le$ 4.0 µg/mL | MP Lot: 2.0 µg/mL P2 Lot: 3.3 µg/mL P3 Lot: 3.1 µg/mL |
| Precision (Repeatability) | Not explicitly stated, but consistent low CVs are expected | TDM Control 1: Mean 7.45 µg/mL, SD 0.4 µg/mL, CV 5.2% TDM Control 2: Mean 21.5 µg/mL, SD 0.5 µg/mL, CV 2.3% TDM Control 3: Mean 36.2 µg/mL, SD 0.9 µg/mL, CV 2.4% Human Serum 1: Mean 4.82 µg/mL, SD 0.4 µg/mL, CV 8.2% Human Serum 2: Mean 7.95 µg/mL, SD 0.4 µg/mL, CV 5.2% Human Serum 3: Mean 32.1 µg/mL, SD 0.8 µg/mL, CV 2.5% Human Serum 4: Mean 40.0 µg/mL, SD 1.0 µg/mL, CV 2.5% Human Serum 5: Mean 71.4 µg/mL, SD 2.0 µg/mL, CV 2.8% |
| Precision (Intermediate) | Not explicitly stated, but consistent low CVs are expected | TDM Control 1: Mean 7.45 µg/mL, SD 0.5 µg/mL, CV 6.2% TDM Control 2: Mean 21.5 µg/mL, SD 0.8 µg/mL, CV 3.7% TDM Control 3: Mean 35.5 µg/mL, SD 1.1 µg/mL, CV 3.2% Human Serum 1: Mean 4.93 µg/mL, SD 0.5 µg/mL, CV 10.5% Human Serum 2: Mean 7.95 µg/mL, SD 0.5 µg/mL, CV 5.9% Human Serum 3: Mean 32.1 µg/mL, SD 1.1 µg/mL, CV 3.4% Human Serum 4: Mean 39.5 µg/mL, SD 1.1 µg/mL, CV 2.9% Human Serum 5: Mean 71.4 µg/mL, SD 2.2 µg/mL, CV 3.1% |
| Linearity | Pearson correlation coefficient (R) close to 1, slope close to 1, intercept close to 0 | Serum: y=1.000x-0.000, R=0.9985 Plasma: y=1.000x-0.000, R=0.9976 |
| Measuring Range | 4.0 to 80.0 µg/mL | 4.0 to 80.0 µg/mL (Claimed, consistent with linearity results) |
| Matrix Comparison | Strong correlation (r value close to 1) between plasma and serum measurements | Serum vs. Li-heparin: y = 1.01x -0.3, r = 0.996 Serum vs. K2-EDTA: y = 0.99x -0.0, r = 0.996 Serum vs. K3-EDTA: y = 1.00x - 0.3, r = 0.995 |
| Endogenous Interference | No significant interference up to stated levels | Hemolysis: No interference up to H index of 1000 (1000 mg/dL hemoglobin) Lipemia: No interference up to L index of 1000 (1000 mg/dL triglycerides) Icterus (Unconjugated Bilirubin): No interference up to I index of 60 (60 mg/dL or 1026 umol/L) Icterus (Conjugated Bilirubin): No interference up to I index of 60 (60 mg/dL or 1026 umol/L) |
| Drug Interference | No interference up to specified concentrations | No interference observed for a list of common drugs at specified concentrations (e.g., Acetylsalicylic acid 1000 mg/L, Acetaminophen 200 mg/L, Heparin 5000 U/L, etc.) |
| Method Comparison to Predicate | Strong correlation with predicate device, Passing Bablok regression results with slope close to 1 and intercept close to 0 | y = 0.993x + 0.641, r = 0.994 |
2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Detection Limit (LoB, LoD):
- LoB: 60 measurements (5-fold determinations per run, 6 runs over 3 days, across one or two instruments) per lot.
- LoD: 30 samples/measurements (5 serum samples, 6 runs over 3 days, 1-fold or 2-fold determination per run, across one or two instruments) per lot.
- LoQ: 15 serum samples, tested in two aliquots over 6 runs for 4 days.
- Precision: Not explicitly stated, but "two runs per day for $\geq$ 21 days" were performed. The number of samples for controls (3) and human serum (5) are listed, with replicates per run not specified but implied to be sufficient for precision calculations.
- Linearity: Sixteen levels (dilution series from a human serum sample pool and diluent) were prepared. The process was repeated for plasma samples.
- Matrix Comparison: 67 full tubes and 9 half-filled tubes of serum and plasma from a single donor. (K2-EDTA plasma had 10 half-filled tubes).
- Interferences (H, L, I Indices): Two human serum sample pools spiked with Vancomycin. An 11-step dilution series prepared for each interferent, with 3 aliquots per level tested.
- Interferences (Drugs): Two human serum sample pools spiked with Vancomycin. Tested with 3 replicates.
- Method Comparison to Predicate: 125 single native human serum samples from patients taking Vancomycin. 8 additional native Vancomycin samples were spiked, and 1 sample diluted to cover the range.
The data provenance regarding the country of origin is not specified. All studies appear to be prospective experimental studies conducted in a controlled lab setting, rather than retrospective patient data analysis.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
This device is an in-vitro diagnostic (IVD) assay for quantitative determination of vancomycin concentration. The "ground truth" for these types of devices is based on established analytical reference methods or assigned values.
- For LoQ, the expected value was determined with Vancomycin LCMS/MS, which is a highly accurate reference method, not expert consensus.
- For Method Comparison to Predicate, the predicate device (ONLINE TDM Vancomycin, K060586) served as the reference standard for comparison, not human experts.
- No human experts were involved in establishing the ground truth for any of these analytical performance studies. These are laboratory-based measurements.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. This is an IVD device for quantitative measurement, not an imaging or qualitative diagnostic device requiring expert adjudication. The "truth" is determined by analytical reference methods or comparison to a predicate device.
5. 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
Not applicable. This is an IVD device for quantitative measurement, not an AI-assisted diagnostic tool for human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
This entire submission describes the standalone performance of the ONLINE TDM Vancomycin Gen.3 assay. The device itself is an automated chemical analyzer system (Roche/Hitachi cobas c systems) that performs the assay, not an AI algorithm. The performance metrics listed (detection limit, precision, linearity, interference, method comparison) are all standalone analytical performance characteristics of the device.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth or reference methods used for evaluation include:
- LCMS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry): Used for determining expected values for the Limit of Quantitation (LoQ).
- Predicate Device (ONLINE TDM Vancomycin, K060586): Used as the comparative reference for the method comparison study.
- Standard Analytical Protocols: Studies like precision, linearity, and interference follow established CLSI guidelines, where the "truth" is defined by the experimental setup (e.g., known concentrations of analytes, spiked interferents).
8. The sample size for the training set
Not applicable. This device is an IVD assay, not a machine learning or AI-based system that requires a "training set" in the conventional sense. The development of such assays involves reagent formulation, optimization, and extensive analytical verification and validation, but not typically "training data" for an algorithm.
9. How the ground truth for the training set was established
Not applicable, as there is no "training set" for an AI algorithm here.
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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is a stylized image of three human profiles facing to the right, stacked on top of each other. The profiles are connected by a flowing line that resembles a wave or a ribbon.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
January 8, 2016
ROCHE DIAGNOSTICS OPERATIONS (RDO) BARBARA MCWHORTER REGULATORY AFFAIRS PRINCIPAL 9115 HAGUE ROAD INDIANAPOLIS IN 46250
Re: K152245
Trade/Device Name: ONLINE TDM Vancomvcin Gen.3 Regulation Number: 21 CFR 862.3950 Regulation Name: Vancomycin test system Regulatory Class: II Product Code: LEH Dated: December 9, 2015 Received: December 10, 2015
Dear Barbara Mc Whorter:
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 (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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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) K152245
Device Name ONLINE TDM Vancomycin Gen.3
Indications for Use (Describe)
In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems.
A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.
Type of Use (Select one or both, as applicable)
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) |
|---|
| ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
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510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter Name | Roche Diagnostics Operations (RDO) |
|---|---|
| Address | 9115 Hague RoadIndianapolis, IN, 46250, USA |
| Contact | Barbara McWhorterPhone: (317) 521-2336FAX: (317) 521-2324Email: Barbara.McWhorter@roche.com |
| Date Prepared | July 31st, 2015 |
| Proprietary Name | ONLINE TDM Vancomycin Gen.3 |
| Common Name | Immunoassay, Vancomycin |
| Classification Name | Clinical Toxicology Test Systems, Class II |
| Product Codes | LEH, 21 CFR § 862.3950 |
| Predicate Devices | ONLINE TDM Vancomycin, K060586 |
| EstablishmentRegistration | 1823260, Roche Diagnostics Operations Inc. |
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1. DEVICE DESCRIPTION
The ONLINE TDM Vancomycin Gen.3 is a two reagent assay for the in vitro quantitative determination of vancomycin in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles in solution (KIMS). A competitive reaction takes place between the drug conjugate and vancomycin in the serum sample for binding to the vancomycin antibody on the microparticles. The resulting kinetic interaction of microparticles is indirectly proportional to the amount of drug present in the sample.
2. INDICATIONS FOR USE
In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems.
A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.
3. TECHNOLOGICAL CHARACTERISTICS
The assay is based on the kinetic interaction of microparticles in a solution (KIMS). Vancomycin antibody is covalently coupled to microparticles and the drug derivative is linked to a macromolecule. The kinetic interaction of microparticles in solutions is induced by binding of drug-conjugate to the antibody on the microparticles and is inhibited by the presence of Vancomycin in the sample. A competitive reaction takes place between the drug conjugate and Vancomycin in the serum sample for binding to the Vancomycin antibody on the microparticles. The resulting kinetic interaction of microparticles is indirectly proportional to the amount of drug present in the sample.
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Reagents - working solutions:
- . R1 Vancomycin conjugate; piperazine-N,N-bis (2-ethanesulfonic acid) (PIPES) buffer, pH 7.2; preservative; stabilizer
- R2 Anti-Vancomycin antibody (mouse monoclonal); latex microparticle; 3 -(Nmorpholino) propane sulfonic acid (MOPS) buffer, pH 7.2; stabilizer
4. PREDICATE DEVICE
The predicate device, manufactured by Siemens, which Roche Diagnostics claims substantial equivalence to, is the ONLINE TDM Vancomycin assay. This was cleared in K060586 as a Traditional 510(k) on the Roche/Hitachi 917 and Modular P analyzer systems. The ONLINE TDM Vancomycin assay was then applied to the cobas c 501 analyzer system. FDA designated this CLIA categorization as moderate complexity with the K060373/A001.The following table compares the features of the candidate device to the predicate device.
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:ONLINE TDM VancomycinK060586 | Candidate Device:ONLINE TDM VancomycinGen.3 |
| Intended Use | The ONLINE TDM Vancomycinassay is for the quantitativedetermination of vancomycin inhuman serum or plasma on Rocheautomated clinical chemistryanalyzers. | In vitro test for the quantitativedetermination of vancomycin inserum and plasma onRoche/Hitachi cobas c systems. |
| Analyzer Systems | Hitachi / Roche Modular P and 917cobas c 501 (K060373/A001) | cobas c 501 |
| Sample Types | Serum: Collect serum usingstandard sampling tubes.Plasma:Potassium (K2 or K3)EDTA,sodium citrate, or fluorideoxalate plasma. | SerumPlasma: K2- or K3-EDTA, lithiumheparin. |
| Assay Comparison | ||
| Feature | Predicate Device:ONLINE TDM VancomycinK060586 | Candidate Device:ONLINE TDM VancomycinGen.3 |
| Test Principle | The assay is based on ahomogeneous enzyme immunoassaytechnique used for the quantitativeanalysis of vancomycin in humanserum or plasma. The assay is basedon competition between drug in thesample and drug labeled with theenzyme glucose-6-phosphatedehydrogenase (G6PDH) forantibody binding sites. Enzymeactivity decreases upon binding tothe antibody, so the drugconcentration in the sample can bemeasured in terms of enzymeactivity. Active enzyme convertsoxidized nicotinamide adeninedinucleotide (NAD) to NADH,resulting in an absorbance changethat is measuredspectrophotometrically. Endogenousserum G6PDH does not interferebecause the coenzyme functionsonly with the bacterial (Leuconostocmesenteroids) enzyme employed inthe assay. | The assay is based on the kineticinteraction of microparticles in asolution (KIMS). Vancomycinantibody is covalently coupled tomicroparticles and the drugderivative is linked to amacromolecule. The kineticinteraction of microparticles insolutions is induced by binding ofdrug-conjugate to the antibody onthe microparticles and is inhibitedby the presence of Vancomycin inthe sample. A competitive reactiontakes place between the drugconjugate and Vancomycin in theserum sample for binding to theVancomycin antibody on themicroparticles. The resultingkinetic interaction ofmicroparticles is indirectlyproportional to the amount of drugpresent in the sample. |
| Reagent Shelf LifeStability | 2-8 °C until expiration date | Same |
| Reagent On-BoardStability | 60 days opened and refrigerated onthe analyzer. Do not freeze. | 12 weeks on-board in use andrefrigerated on the analyzer. Donot freeze. |
| Measuring Range | 1.7 to 80 µg/mL(based on LDL) | 4.0 to 80 µg/mL(based on LoQ) |
| Traceability | This method has been standardizedagainst USP reference standards. | Same |
| Calibrator | Preciset TDM 1 calibrator(Previously cleared 510(k):K031856) | Same |
| CalibrationFrequency | • after reagent bottle change• after reagent lot change• as required following qualitycontrol procedures | • after lot change• after 6 weeks• as required following qualitycontrol procedures |
| Controls | TDM Control Set(Previously cleared 510(k): K060429and K070200) | Same |
| Assay Comparison | ||
| Feature | Predicate Device:ONLINE TDM VancomycinK060586 | Candidate Device:ONLINE TDM VancomycinGen.3 |
| Lower Limits ofMeasurement | Lower Detection Limit = 1.7µg/mL (1.2 µmol/L) | LoB = 1.0 µg/mL (0.69 µmol/L)LoD = 1.5 µg/mL (1.04 µmol/L)LoQ = 4.0 µg/mL (2.76 µmol/L) |
| ReagentComposition | R1 Enzyme ReagentVancomycin labeled with bacterialG6PHDH in bufferR2 Antibody/Substrate ReagentAnti-vancomycin antibody (mousemonoclonal), G6P and NAD inbuffer | R1 Vancomycin conjugate;piperazine-N,N'-bis (2ethanesulfonic acid) (PIPES)buffer, pH 7.2; preservative;stabilizerR2 Anti-Vancomycin antibody(mouse monoclonal); latexmicroparticle; 3-(N-morpholino)propane sulfonic acid (MOPS)buffer, pH 7.2; stabilizer |
Table 1: Substantial Equivalence – Assav Comparison
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5. NON-CLINICAL PERFORMANCE EVALUATION
The following performance data were provided in support of the substantial equivalence determination:
Detection Limit: LoB, LoD and LoQ according to CLSI EP17-A2
Precision according to CLSI EP5-A2
Linearity according to CLSI EP6-A
Matrix Comparison - Anticoagulants
Interferences - H, L and I Indices
Interference - Drugs
Method Comparison to Predicate
5.1. Detection Limit
LoB, LoD, and LoQ studies were performed based upon CLSI EP17-A2.
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LoB:
LoB (Limit of Blank) corresponds to the concentration below which analyte-free samples are found with a probability of 95%.
For MP Lot: The diluent is measured with 5-fold determinations per run on two instruments. Six runs distributed over 3 days were performed. Data analysis was based on determination of the 95th percentile of the 60 measured values.
For P2 and P3 Lots: The diluent is measured with 5-fold determinations per run on one instrument. Six runs distributed over 3 days were performed. Data analysis was based on determination of the 95th percentile of the 60 measured values.
LoD:
LoD (Limit of Detection) corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95 %).
For MP Lot: Five serum samples with low analyte content spiked with Vancomycin (with concentrations ranging from LoB to approx. 4 times specified LoB) were measured with 1-fold determination per run on two instruments. Six runs distributed over 3 days were performed.
For P2 and P3 Lots: Five serum samples with low analyte content spiked with Vancomycin (with concentrations ranging from LoB to approx. 4 times specified LoB) were measured with 2-fold determination per run on one instrument. Six runs distributed over 3 days were performed.
LoQ:
LoQ (Limit of Quantitation) is the lowest amount of analyte in a sample that can be detected quantitatively within specified precision and accuracy ranges.
Fifteen serum samples were prepared which cover the concentration range between LoB and 2x LoQ. Those samples were tested in two aliquots. Six runs over 4 days were performed. Expected value is determined with Vancomycin LCMS/MS.
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| Result MP Lot(μg/mL) | Result P2 Lot(μg/mL) | Result P3 Lot(μg/mL) | Claim(μg/mL) | |
|---|---|---|---|---|
| Limit of Blank (LoB) | 0.6 | 0.7 | 0.5 | 1.0 |
| Limit of Detection (LoD) | 1.4 | 1.3 | 1.1 | 1.5 |
| Limit of Quantitation (LoQ) | 2.0 | 3.3 | 3.1 | 4.0 |
Table 2: LoB, LoD, and LoQ Experimental Determination
5.2. Precision according to CLSI EP5-A
Precision experiments were performed in Accordance with CLSI Guideline EP5-A2. Two runs per day for $\geq$ 21 days were performed on the same analyzer. Repeatability and intermediate precision was calculated. The serum samples were randomized in each run separately. The data set was completed for the 21 days. For each sample, the following were calculated: Mean, Repeatability and Intermediate precision as CV and SD values.
| Specimen | Mean (µg/mL) | SD (µg/mL) | CV (%) |
|---|---|---|---|
| TDM Control 1 | 7.45 | 0.4 | 5.2 |
| TDM Control 2 | 21.5 | 0.5 | 2.3 |
| TDM Control 3 | 36.2 | 0.9 | 2.4 |
| Human Serum 1 | 4.82 | 0.4 | 8.2 |
| Human Serum 2 | 7.95 | 0.4 | 5.2 |
| Human Serum 3 | 32.1 | 0.8 | 2.5 |
| Human Serum 4 | 40.0 | 1.0 | 2.5 |
| Human Serum 5 | 71.4 | 2.0 | 2.8 |
Table 3: Repeatability Precision Summary
Table 4: Intermediate Precision Summary
| Specimen | Mean ( $\mu$ g/mL) | SD ( $\mu$ g/mL) | CV (%) |
|---|---|---|---|
| TDM Control 1 | 7.45 | 0.5 | 6.2 |
| TDM Control 2 | 21.5 | 0.8 | 3.7 |
| TDM Control 3 | 35.5 | 1.1 | 3.2 |
| Human Serum 1 | 4.93 | 0.5 | 10.5 |
| Human Serum 2 | 7.95 | 0.5 | 5.9 |
| Human Serum 3 | 32.1 | 1.1 | 3.4 |
| Human Serum 4 | 39.5 | 1.1 | 2.9 |
| Human Serum 5 | 71.4 | 2.2 | 3.1 |
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Linearity according to CLSI EP6-A 5.3.
A dilution series were prepared from a human serum sample pool and diluent (Preciset TDM1Diluent). The dilution series were prepared to obtain sixteen levels* (including the high concentration pool and diluent). The diluted samples shall span the measuring range including a non-zero sample below the measuring range and a sample over the measuring range. The process was repeated for plasma samples.
- Due to the importance of the trough concentration (ca. 5 – 10 $\mu$g/mL Vancomycin) and due to the unknown LoQ before the measurement, more samples were chosen in the low concentration range.
The calculation is according to the CLSI guideline EP6-A. All measurement data of the dilution steps were calculated by linear regression without weighting.
| Sample Type | Linear Regression Equation | Claimed Measuring Range |
|---|---|---|
| Serum | y=1.000x-0.000Pearson correlation coefficient (R)=0.9985 | 4.0 to 80.0 µg/mL |
| Plasma | y=1.000x-0.000Pearson correlation coefficient (R)=0.9976 | 4.0 to 80.0 µg/mL |
Table 5: Linearity Results
5.4. Matrix Comparison - Anticoagulants
Each pair of serum and plasma of a single donor are spiked with Vancomycin. Included in the data are 67 full tubes and 9 half-filled tubes (except K2-EDTA plasma, which had 10 tubes). The half-filled and filled sample tubes are also from one donor. Method comparison is executed by taking the serum as reference. Only samples within the measuring range were used.
The following method comparisons are provided:
- K2-EDTA plasma vs serum ●
- K3-EDTA plasma vs serum
- Li-Heparin plasma vs serum ●
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Table 6: Matrix Comparison
| Anticoagulant | Correlation |
|---|---|
| Serum vs. Li-heparin | $y = 1.01x -0.3, r = 0.996$ |
| Serum vs. K2-EDTA | $y = 0.99x -0.0, r = 0.996$ |
| Serum vs. K3-EDTA | $y = 1.00x - 0.3, r = 0.995$ |
5.5. Interferences - H, L and I Indices
The effect on quantitation of analyte in the presence of endogenous interfering substances is determined at two Vancomycin concentrations and a dilution set of the added interfering substances. Interfering substances evaluated include:
Hemolysis up to an H index of 1000
Lipemia up to an L index of 1000
Icterus/Bilirubin up to an I index of 60
High concentrated stock solutions of the interference substances were prepared in a suitable solvent. Two human serum sample pools were spiked with the defined Vancomvcin concentrations and divided into two aliquots. The potential interfering substance is added to one aliquot, while the other aliquot was mixed with the same amount of solvent without the interfering substance. A dilution series was prepared with 11 dilution steps for each interferent by mixing the 2 aliquots. Three aliquots per level were tested in 1 run on 1 instrument and 1 lot.
The parts containing the interfering substance will have the same Vancomycin concentrations as the aliquots containing no interfering substance. When diluting those two aliquots the Vancomycin concentration will remain constant while the concentration of interferent will vary. Thus the effect of increasing concentrations of interferent can be determined.
Median of the measured results were compared to the expected result (aliquot with no interfering substance) and the recovery is determined (paired difference testing).
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| Interferent | No interference up to |
|---|---|
| Hemolysis | Level 1: 1161 H IndexLevel 2: 1133 H Index |
| Lipemia | Level 1: 1234 L IndexLevel 2: 1232 L Index |
| Unconjugated Bilirubin | Level 1: 79 I IndexLevel 2: 82 I Index |
| Conjugated Bilirubin | Level 1: 77 I IndexLevel 2: 75 I Index |
Table 7: Interference from Endogenous Substances
Labeling Claim for Endogenous Substances:
Icterus:
No significant interference up to an I index of 60 for conjugated bilirubin and unconjugated bilirubin (approximate conjugated and unconjugated bilirubin concentration: 60 mg/dL or 1026 umo1/L).
Hemolysis:
No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 1000 mg/dL or 622 umol/L).
Lipemia (Intralipid):
No significant interference up to an L index of 1000. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration. No significant interference from triglycerides up to 1000 mg/dL (11.4 mmol/L).
5.6. Interferences – Drugs
Two human serum sample pools spiked with the defined Vancomycin concentrations were divided into two aliquots. One aliquot of each concentration were used as the reference sample for Vancomycin concentration and were not spiked with the drugs but the solvent for the drug.
The other aliquots, with either the high or low Vancomycin concentration, were spiked with the respective amount of drug. The Vancomycin concentration of the spiked aliquots were tested with 3 replicates in one run, 1 reagent lot and one instrument. The defined pharmaceutical compounds were spiked into samples with concentrations according to EP7-A2 or higher concentrations.
{13}------------------------------------------------
| Drug | Highest Concentration Shown Not to Interfere withVancomycin |
|---|---|
| Acetylsalicylic acid | 1000 mg/L |
| Acetaminophen | 200 mg/L |
| Acetylcysteine | 1660 mg/L |
| Ampicillin-sodium | 1000 mg/L |
| Ascorbic acid | 300 mg/L |
| Cefoxitin | 2500 mg/L |
| Cyclosporine | 5 mg/L |
| Doxycycline | 50 mg/L |
| Heparin | 5000 U/L |
| Ibuprofen | 500 mg/L |
| Levodopa | 20 mg/L |
| Methyldopa | 20 mg/L |
| Metronidazole | 200 µg/mL |
| Methotrexate | 455 µg/mL |
| Phenylbutazone | 400 mg/L |
| Rifampicin | 60 mg/L |
| Theophyllin | 100 mg/L |
Table 8: Common Drug Interferences
5.7. Method Comparison to Predicate
One hundred twenty five single native human serum samples of patients taking Vancomycin covering the reportable range were tested. Eight of these native Vancomycin samples were spiked with Vancomycin and 1 sample diluted to cover the range. All samples were tested for icteric, lipemic and hemolytic interference.
The samples were tested in singlicate on the candidate and predicate device (cobas c 501).
The data was evaluated using Passing Bablok Regression analysis.
$$\mathbf{y} = 0.993\mathbf{x} + 0.641, \mathbf{r} = 0.994$$
CONCLUSIONS 6.
The submitted information in this premarket notification supports a substantial equivalence decision.
§ 862.3950 Vancomycin test system.
(a)
Identification. A vancomycin test system is a device intended to measure vancomycin, an antibiotic drug, in serum. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy.(b)
Classification. Class II.