Human IgM Kit for use on SPAPlus

K191465 · The Binding Site Group , Ltd. · CFN · Jun 27, 2019 · Immunology

Device Facts

• Record ID: K191465
• Device Name: Human IgM Kit for use on SPAPlus
• Applicant: The Binding Site Group , Ltd.
• Product Code: CFN · Immunology
• Decision Date: Jun 27, 2019
• Decision: SESE
• Submission Type: Special
• Regulation: 21 CFR 866.5510
• Device Class: Class 2

Intended Use

This kit is intended for the quantitative in vitro determination of human IgM in human serum, lithium heparin or EDTA plasma, using the Binding Site SPAPLUS turbidimetric analyser. Measurement of IgM aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents. The test results are to be used in conjunction with other clinical and laboratory findings.

Device Story

The Human IgM Kit for use on SPAPLUS is an in vitro diagnostic reagent system used to quantify human IgM levels in serum or plasma samples. The device utilizes immunoturbidimetry: patient samples are mixed with goat anti-human IgM antiserum, forming insoluble antigen-antibody complexes. The SPAPLUS analyzer passes light through the suspension; the amount of transmitted light, measured by a photodiode, is inversely proportional to the IgM concentration. The system automatically calculates concentrations using a stored calibration curve. It is intended for use in clinical laboratory settings by trained personnel. Results assist clinicians in evaluating protein metabolism and immune function. The device is a modification of a previously cleared kit (K082129), featuring a change in the source of the detection antibody (goat vs. sheep) and the antibody resting buffer composition. Performance is validated through precision, linearity, and method comparison studies against the predicate.

Clinical Evidence

No clinical studies were performed. Analytical performance was established via bench testing, including precision (repeatability, within-lab, between-instrument, and between-lot), linearity, and method comparison against the predicate. Method comparison (n=133) showed a correlation coefficient of 0.996 and a mean bias of -2.18%. Reference interval transfer was validated using 20 healthy donor samples.

Technological Characteristics

Turbidimetric immunoassay; utilizes goat anti-IgM antisera. Automated system for use on SPAPlus analyzer. Fundamental technology is unchanged from predicate device.

Indications for Use

Indicated for the quantitative determination of human IgM in serum for the assessment of immunoglobulin levels in patients.

Regulatory Classification

Identification

An immunoglobulins A, G, M, D, and E immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the immunoglobulins A, G, M, D, an E (serum antibodies) in serum. Measurement of these immunoglobulins aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

Predicate Devices

• Human IgM Kit for Use on SPAPlus (K082129)

Submission Summary (Full Text)

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June 27, 2019

The Binding Site Group Ltd. Natasha Verhaak Regulatory Affairs Officer 8 Calthorpe Road Edgbaston, B15 1qt Gb UK

Re: K191465

Trade/Device Name: Human IgM Kit for use on SPAPlus Regulation Number: 21 CFR 866.5510 Regulation Name: Immunoglobulins A. G. M. D. and E immunological test system Regulatory Class: Class II Product Code: CFN Dated: May 28, 2019 Received: June 3, 2019

Dear Natasha Verhaak:

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

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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) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). 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 (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

Doug Jeffery, Ph.D. Acting Deputy Director Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

#### Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: 06/30/2020 See PRA Statement below.

510(k) Number (if known) K191465

Device Name Human IgM Kit for use on SPAPlus

Indications for Use (Describe)

This kit is intended for the quantitative in vitro determination of human IgM in human serum, lithium heparin or EDTA plasma, using the Binding Site SPAPLUS turbidimetric analyser. Measurement of IgM aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents. The test results are to be used in conjunction with other clinical and laboratory findings.

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

Z Prescription Use (Part 21 CFR 801 Subpart D)

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

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# Human IgM Kit for Use on SPAPIus Special 510(k) Submission Summary

Natasha Verhaak Regulatory Affairs Officer The Binding Site Group Ltd. 8 Calthorpe Road Edgbaston Birmingham, West Midlands, B15 1QT, UK Telephone: [phone] Email: [e-mail] or [e-mail]

#### A. 510(k) Number:

K191465

#### B. Purpose for Submission:

Modification to an existing device

#### C. Measurand:

lgM

## D. Type of Test:

Quantitative immunoturbidimetry

#### E. Applicant:

The Binding Site

# F. Proprietary and Established Names:

Human IgM kit for use on SPAPLUS®

#### G. Regulatory Information:

- 1. Regulation section: 21 CFR 866.5510, Immunoglobulins A, G, M, D, and E immunological test system
- 2. Classification: Class II
- 3. Product code: CFN - method, nephelometric, immunoglobulins (G, A, M)
- 4. Panel: Immunology (82)

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#### H. Intended use:

- 1. Intended use(s):
This kit is intended for the quantitative in vitro determination of human serum, lithium heparin or EDTA plasma, using the Binding Site SPAPLUS turbidimetric analyser. Measurement of IgM aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents. The test results are to be used in conjunction with other clinical and laboratory findings.

The intended use is the same as the cleared kit and has not been changed.

## 2. Indication(s) for use:

Same as Intended use.

- 3. Special conditions for use statement(s):
Prescription use only

- 4. Special instrument requirements:
The Binding Site SPAPIus analyser

#### l. Device Description:

The SPAPlus IgM Kit comprises the following reagents:

Antiserum: Goat Anti-IgM is supplied in stabilised liquid form. Preservatives: 0.099% sodium azide, 0.1% E-amino-n-caproic acid (EACA), 0.5% BSA and 0.01% benzamidine.

Calibrator and Controls: Pooled human serum, supplied in stabilised liquid form. Contain 0.099% sodium azide. 0.1% EACA and 0.01% benzamidine as preservatives. The concentration given on the quality control certificate has been obtained by comparison with the DA470k international reference material.

Reaction Buffer: Containing 0.099% sodium azide as a preservative.

#### J. Substantial equivalence information:

- 1. Predicate device name(s) and 510(k) number(s): Human IgM Kit for Use on SPAPIus (K082129)

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#### 2. Comparison with predicate:

| Similarities | | |
|--------------------------|--------------------------------------------------------|-------------------|
| Item | Modified device | Registered device |
| Intended Use | Quantitative in vitro measurement of<br>IgM | Same |
| Test Method | Turbidimetric | Same |
| Specimen Type | Serum, lithium heparin, EDTA plasma | Same |
| Assay type | Quantitative | Same |
| On-board Stability | 30 days | Same |
| Calibration traceability | DA470k | Same |
| Measuring Range | 0.2 - 7.5 (standard assay dilution) | Same |
| Reference Interval | 0.35 - 2.42 g/L | Same |
| Instrument | SPAPlus | Same |
| Antigen excess capacity | 56.4 g/L | Same |
| Calibration method | Pooled human sera | Same |
| Controls | Pooled human sera | Same |
| Open vial stability | 3 months | Same |
| Antibody processing | Affinity purification, specificity<br>confirmed by IEP | Same |

| Differences | | |
|---------------------------------|---------------------|-------------------|
| Item | Modified device | Registered device |
| Source of detection<br>antibody | Goat antibody | Sheep antibody |
| Antibody resting<br>buffer | GBS and PBS (50:50) | GBS |

#### K. Standards and Guidance documents referenced:

CLSI EP17-A2 Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline

CLSI EP5-A3 Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Second Edition

CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents- 1st Edition

#### L. Test Principle:

The determination of soluble antigen concentration by turbidimetric methods involves the reaction with specific antiserum to form insoluble complexes. When light is passed through the suspension formed a portion of the light is transmitted and focused onto a photodiode by an optical lens system. The amount of transmitted light is indirectly proportional to the specific protein concentration in the test sample. Concentrations are automatically calculated by reference to a calibration curve stored within the instrument.

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#### M. Performance Characteristics (if/when applicable):

- 1. Analytical performance:
- Precision/Reproducibility: a.

The precision studies were based on CLSI EP5-A3 Evaluation of Precision Performance of Clinical Quantitative Measurement Methods as was agreed in pre-submission meeting Q171503.

The repeatability and within laboratory study was performed over 20 working days, with 2 runs per day and 2 reps per run. 3 different samples were assessed using 1 reagent lot on 1 analyser.

| Repeatability and Within Laboratory Summary | | | | | | | | | | |
|---------------------------------------------|----|-------------|------------|------|-------------|------|-------------|------|-------|------|
| | N | Mean (mg/L) | Within run | | Between run | | Between day | | Total | |
| | | | SD | CV % | SD | CV % | SD | CV % | SD | CV % |
| Level 1 | 80 | 0.344 | 0.013 | 3.6 | 0.005 | 1.5 | 0.016 | 4.7 | 0.021 | 6.1 |
| Level 2 | 80 | 2.949 | 0.050 | 1.7 | 0.040 | 1.3 | 0.100 | 3.4 | 0.119 | 4.0 |
| Level 3 | 80 | 5.975 | 0.087 | 1.4 | 0.086 | 1.4 | 0.123 | 2.1 | 0.173 | 2.9 |

Repeatability and Within Laboratory Results:

The between instrument precision study was performed over 6 working days. 2 instruments were tested each day, with 2 replicates per instrument. 3 different samples were assessed using 1 reagent lot on a total of 3 different instruments.

Between Instrument Results:

| | N | Mean<br>(mg/L) | Between<br>Instrument | |
|---------|----|----------------|-----------------------|------|
| | | | SD | CV % |
| Level 1 | 24 | 0.340 | 0.008 | 2.4 |
| Level 2 | 24 | 2.994 | 0.162 | 5.4 |
| Level 3 | 24 | 6.184 | 0.288 | 4.8 |

The between lot precision study was performed over 6 working days. 2 lots were tested each day, with 2 replicates per lot. 3 different samples were assessed using 2 reagent lots on 1 analyser.

Between Lot Results:

| | N | Mean<br>(mg/L) | Between Lot | |
|---------|----|----------------|-------------|------|
| | | | SD | CV % |
| Level 1 | 24 | 0.318 | 0.009 | 3.0 |
| Level 2 | 24 | 3.007 | 0.090 | 3.0 |
| Level 3 | 24 | 6.236 | 0.291 | 4.7 |

The above results do not indicate any change in performance compared to the device cleared in K082129. The precision claims in the product insert therefore still accurately represent the performance of the modified kit and do not need to be amended.

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## b. Linearity/assay reportable range:

A linearity study was carried out as per the original submission (K082129) where a dilution series was produced from a high pool with a known concentration of 8.64 g/L and a low pool with a concentration of 0.15g/L. Each diluted sample was tested in six replicates and a linear regression analysis was carried out. The linear regression equation was shown to be y = 0.9904x - 0.1583 g/L, with an r value of 0.999.

These results are comparable to those currently presented in the product insert and therefore do not indicate any change in performance compared to the device cleared in K082129. The linearity claims in the product insert therefore still accurately represent the performance of the modified kit and do not need to be amended.

## c. Traceability, Stability, Expected values (controls, calibrators, or methods):

## i) Traceability:

The calibration of the assay is traceable to ERM-DA470k/IFCC.

ii) Kit Stability:

Accelerated Stability

Accelerated stability studies were carried out to verify that the stability of the kit is unchanged in accordance with ISO 23640:2015. 6 replicates of controls, internal reference and samples were tested over a period equivalent to 13-months and analysed in line with EP25-A with a maximum allowable difference of ±15% in order to verify the stability claim of 12 months. Reagents were stored at 37℃ to accelerate the study by a factor of 10.

| Parameter | IR | Control | | Sample | | |
|------------------------------------------|------|---------|------|--------|------|------|
| | | Low | High | 1 | 2 | 3 |
| Accelerated stability<br>achieved (days) | 39 | 39 | 39 | 39 | 47.3 | 39 |
| Equivalent at 4ºC (days) | 384 | 384 | 388 | 390 | 465 | 390 |
| Stability required at 4ºC<br>(days) | 365 | 365 | 365 | 365 | 365 | 365 |
| Decision | Pass | Pass | Pass | Pass | Pass | Pass |

#### Accelerated Stability Results

Real Time Stability

To further support the results of the accelerated stability testing, a real time stability study is currently being carried out in accordance with EP25-A and as was agreed in pre-submission meeting Q171503.

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#### On Board Stability

On board stability studies were carried out as per the original 510(k) submission and showed no difference in the cleared on board stability claim

#### d. Detection limit.

The limit of quantitation (LoQ) for this assay is defined as the bottom of the measuring range, 0.1 g/L at minimum (1/10) sample dilution, which is equivalent to 0.2 g/L at standard (1/20) dilution. The LoQ validation study was based on CLSI EP17-A2 Evaluation of the Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - 2nd Edition in accordance with pre-submission meeting Q171503. Four samples were tested using two reagent lots. The LoQ claim was validated by all the samples reporting within the acceptance criteria of an allowable CV of 10%.

The limit of detection (LoD) represents the lowest measurable analyte level that can be distinguished from zero, this was estimated as 0.004 g/L in the original submission and the limit of blank (LoB) was estimated to be 0.001g/L. Additional testing was carried out following the antisera change and no change in performance was observed.

The results generated do not indicate any change in performance compared to the device cleared in K082129. The LoB, LoD and LoQ claims in the product insert therefore still accurately represent the performance of the modified kit and do not need to be amended.

e. Analytical specificity:

As per original submission (K082129)

f. Assay cut-off:

Not determined

#### 3. Comparison studies:

a. Method comparison with predicate device:

A comparison study was performed by analysing 89 serum samples and 44 plasma samples using the modified IgM Kit for use on the SPAPLus and the unmodified kit which is already commercially available. The study was carried out in accordance with pre-submission meeting Q171503. Bland Altman and Passing Bablok regression analysis generated the following results:

| Bland Altman Mean Bias | 95% Limits of Agreement | |
|------------------------|-------------------------|------------------|
| -2.18% | -16.55% to 12.18% | |
| Passing Bablok | Slope 95% CI | Intercept 95% CI |
| y= 0.964x + 0.008 | 0.947 to 0.986 | -0.008 to 0.028 |

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| Correlation coefficient |
|-------------------------|
| 0.996 |

| Predicate Sample Ranges | Test Samples Ranges |
|-------------------------|---------------------|
| 0.107 - 11.780 | 0.116 - 11.066 |

The above results do not indicate any change in performance compared to the device cleared in K082129. The comparison claims in the product insert therefore still accurately represent the performance of the modified kit and do not need to be amended.

#### b. Matrix comparison:

As per the original submission (K082129), no difference between matrices were observed.

#### 3. Clinical studies:

a. Clinical Sensitivity: None determined

b. Clinical specificity: None determined

c. Other clinical supportive data (when a. and b. are not applicable): Not applicable

- 4. Clinical cut-off:
None determined

#### 5. Expected values/Reference range:

Following the protocol agreed in Q171503, 20 samples from apparently healthy US donors were tested using the modified assay. The acceptance criteria for the transfer is ≤2 samples falling outside of the limits of the reference interval to be transferred.

Of the 20 samples tested, 19 gave results within the reference interval, ranging from 0.364 to 1.736 g/L. One sample gave a result of 0.348 g/L, which is on the lower boundary of the reference interval (0.35 g/L). The results of this study therefore meet the acceptance criteria and indicate that the reference interval can be transferred from the originally cleared device.

This is further supported by the results of the comparison study. When considering the lower limit of the reference interval, all samples tested gave clinically concordant results.

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#### N. Proposed Labelling:

The labelling is sufficient, and it satisfies the requirements of 21 CFR Part 809.10.

The labelling is the same as the cleared kit and has not been changed.

#### O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.