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The BioPlex 2200 ToRC IgG kit is a multiplex flow immunoassay intended for the quantitative detection of IgG antibodies to Toxoplasma gondii (T. gondii) and Rubella. and the qualitative detection of IgG antibodies to Cytomegalovirus (CMV) in human serum and EDTA or heparinized plasma.

The ToRC IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the determination of serological status to.T. gondii, Rubella and CMV. This kit is not intended for use in screening blood or plasma donors.

Performance characteristics for T. gondii and Rubella have not been evaluated in immunocompromised or immunosuppressed individuals. Performance characteristics for CMV have not been evaluated in immunosuppressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at a point of care.

The BioPlex® 2200 ToRC IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. "ToRC" is an acronym for individual tests to detect antibodies to Toxoplasma gondii (T. gondii), Rubella, and Cytomegalovirus (CMV). Three (3) different populations of dyed beads are coated with cell lysates bearing T. gondii, Rubella, or CMV antigens.

The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel: the mixture is incubated at 37°C. After a wash cycle, anti-human IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads, and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the . fluorescence of the attached PE. Raw data are calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, Internal Standard Bead (ISB), Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma.

The instrument is calibrated using a set of six (6) distinct calibrator vials. the BioPlex 2200 ToRC IgG Calibrator Set. For T. gondii and Rubella, six (6) vials, representing six (6) different levels of antibody concentrations, are used for quantitative calibration, and results for patient samples are expressed in IU/mL. For T. gondii, results of ≤ 9 IU/mL are negative, 10 and 11 IU/mL are equivocal, and results of > 12 IU/mL are reported as positive. For Rubella, results of ≤ 7 IU/mL are reported as negative, 8 and 9 IU/mL are equivocal, and ≥ 10 IU/mL are reported as positive. For CMV, four (4) vials, representing four (4) different antibody concentrations, are used for qualitative calibration. CMV results are expressed as an antibody index (AI) and results of ≤ 0.8 AI are negative, 0.9 and 1.0 AI are equivocal, and results of ≥ 1.1 AI are reported as positive.

The BioPlex 2200 ToRC IgG Control Set includes a negative control as well as two (2) multi-analyte positive controls. The BioPlex ToRC IgG Low Positive Control contains antibodies for T. gondii, Rubella and CMV and the BioPlex ToRC IgG High Positive Control contains antibodies for T. gondii and Rubella. The BioPlex ToRC IgG Positive Controls are manufactured to give positive results, with values above the cut-off for each specific analyte. The BioPlex ToRC IgG Negative Control is manufactured to give negative results, with values below the cut-off for each specific analyte. The recommended frequency for performing quality control is once every 24-hour testing period. Performing quality control is also necessary after each new assay calibration and certain service procedures.

This document describes a Special 510(k) submission for a modification to the BioPlex® 2200 ToRC IgG kit. The only change being made is the frequency of Reagent Pack Quality Control (QC) testing from once per pack and per day to once per day and per new reagent pack lot.

Therefore, the acceptance criteria and study information provided below relate to demonstrating that this change in QC frequency does not negatively impact the performance of the device and maintains substantial equivalence to the predicate device.

1. A table of acceptance criteria and the reported device performance

The document states that the modification involved a change in QC testing frequency, and the "Based on the conclusion of the risk management report, the modified QC procedure fulfills the requirements of the specifications of the design control process." This implies that the acceptance criteria are met if the device maintains its original performance characteristics with the new QC frequency. The performance characteristics of the original device are not provided in this document, as the focus is solely on supporting the change in QC frequency.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document does not specify a separate "test set" in the traditional sense for evaluating the performance of the modified device against a ground truth. Instead, the justification for the change in QC frequency relies on a Risk Analysis method and FMEA. Therefore, there is no sample size for an external "test set" and no specific data provenance related to patient samples is mentioned for this particular modification. The study focused on demonstrating equivalence through internal quality control and risk management activities.

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)

Not applicable. As described above, there was no external "test set" with a ground truth established by experts. The substantiation for this modification comes from internal risk assessment and design control activities.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not applicable. There was no external "test set" requiring adjudication.

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 device is an in vitro diagnostic (IVD) multiplex flow immunoassay system, not an AI-assisted diagnostic tool. Therefore, MRMC studies and human reader improvement with AI are irrelevant to this submission.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This is an IVD device; its performance is inherently "standalone" in the sense that it automates the testing process. The document does not describe separate algorithm-only studies beyond the reported performance of the integrated system. The focus of this 510(k) is a change in QC frequency, not a new algorithm or core performance evaluation.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

Not applicable for this 510(k) modification. The original device's performance would have been established against a ground truth (e.g., reference methods, clinical diagnosis), but this document focuses on demonstrating that the change in QC frequency does not alter those established performance characteristics. The "ground truth" for this submission is the successful completion of the risk management process and the conclusion that the modified QC procedure meets the requirements and maintains substantial equivalence.

8. The sample size for the training set

Not applicable. This is not a machine learning or AI-based device that would typically involve a "training set" for an algorithm.

9. How the ground truth for the training set was established

Not applicable. See point 8.

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The BioPlex™ 2200 ToRC IgG kit is a multiplex flow immunoassay intended for the quantitative detection of IgG antibodies to Toxoplasma gondii (T. gondii) and Rubella, and the qualitative detection of IgG antibodies to Cytomegalovirus (CMV) in human serum and EDTA or heparinized plasma. The ToRC IgG kit is intended for use with the Bio-Rad BioPlex 2200 System. This kit is intended as an aid in the determination of serological status to T. gondii, Rubella and CMV. This kit is not intended for use in screening blood or plasma donors. Performance characteristics for T. gondii and Rubella have not been evaluated in immunocompromised or immunosuppressed individuals. Performance characteristics for CMV have not been evaluated in immunosuppressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at a point of care.

The BioPlex 2200 ToRC IgG Calibrator Set is intended for the calibration of the BioPlex 2200 ToRC IgG Reagent Pack.

The BioPlex 2200 ToRC IgG Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex ToRC IgG Reagent Pack in the clinical laboratory. The performance of the BioPlex 2200 ToRC IgG Control Set has not been established with any other Toxoplasma gondii, Rubella or Cytomegalovirus (CMV) IgG antibody assays.

The BioPlex™ 2200 ToRC IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. "ToRC" is an acronym for individual tests to detect antibodies to Toxoplasma gondii (T. gondii), Rubella, and Cytomegalovirus (CMV). Three (3) different populations of dyed beads are coated with cell lysates bearing T. gondii, Rubella, or CMV antigens.

The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel; the mixture is incubated at 37°C. After a wash cycle, anti-human IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads, and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data are calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, Internal Standard Bead (ISB), Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma.

The instrument is calibrated using a set of six (6) distinct calibrator vials, the BioPlex 2200 ToRC IgG Calibrator Set. For T. gondii and Rubella, six (6) vials, representing six (6) different levels of antibody concentrations, are used for quantitative calibration, and results for patient samples are expressed in IU/mL. For T. gondii, results of ≤ 9 IU/mL are negative, 10 and 11 IU/mL are equivocal, and results of ≥ 12 IU/mL are reported as positive. For Rubella, results of ≤ 7 IU/mL are reported as negative, 8 and 9 IU/mL are equivocal, and ≥ 10 IU/mL are reported as positive. For CMV, four (4) vials, representing four (4) different antibody concentrations, are used for qualitative calibration. CMV results are expressed as an antibody index (Al) and results of ≤ 0.8 Al are negative, 0.9 and 1.0 Al are equivocal, and results of ≥ 1.1 Al are reported as positive.

The BioPlex 2200 ToRC IgG Control Set includes a negative control as well as two (2) multi-analyte positive controls. The BioPlex ToRC IgG Low Positive Control contains antibodies for T. gondii, Rubella and CMV and the BioPlex ToRC IgG High Positive Control contains antibodies for T. gondii and Rubella. The BioPlex ToRC IgG Positive Controls are manufactured to give positive results, with values above the cut-off for each specific analyte. The BioPlex ToRC IgG Negative Control is manufactured to give negative results, with values below the cut-off for each specific analyte. The recommended frequency for performing quality control is once every 24-hour testing period. Performing quality control is also necessary after each new assay calibration and certain service procedures.

Here's an analysis of the provided text, focusing on the acceptance criteria and the study proving the device meets them:

BioPlex™ 2200 ToRC IgG Kit Performance Analysis

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly present a table of "acceptance criteria" but rather describes various performance characteristics evaluated against predetermined principles (e.g., CLSI standards) or by comparison to predicate devices. The "reported device performance" is then presented as the outcome of these evaluations.

Based on the provided text, the most relevant performance characteristics and their reported outcomes are summarized below:

• T. gondii IgG: Within-run 3.9%-9.5%, Total 6.6%-12.3%
• Rubella IgG: Within-run 3.0%-5.0%, Total 5.2%-9.9%
• CMV IgG: Within-run 1.8%-5.6%, Total 3.8%-8.7%
  External Reproducibility:
• T. gondii IgG: Within-run 3.7%-7.7%, Total 4.8%-17.6%
• Rubella IgG: Within-run 4.6%-6.6%, Total 7.2%-10.3%
• CMV IgG: Within-run 2.5%-5.8%, Total 4.4%-12.1%
  Additional Rubella Reproducibility (near cut-off): Within-run 5.2%-9.7% |
  | Linearity | Based on CLSI EP6-A principles. Expectation of acceptable dilution linearity, with all recoveries within ±20% of the predicted value. | Demonstrated acceptable dilution linearity for T. gondii (3-900 IU/mL), Rubella (1-250 IU/mL), and CMV (0.2-8.0 Al). All recoveries within ±20% of the predicted value. Acceptable dilution linearity through the cut-off for T. gondii and Rubella using WHO IgG standards. |
  | Interfering Substances | Based on CLSI EP7-A2 principles. Expectation of no significant interference from tested substances at specified concentrations. | No significant interference observed with tested substances (Hemoglobin, Bilirubin, Cholesterol, Red Blood Cells, Gamma Globulin, Triglyceride, Total Protein, Ascorbic Acid, Heparin, EDTA) at maximum levels. |
  | Cross-Reactivity | Expectation that various disease state samples do not cross-react with the three (3) assays in the BioPlex ToRC IgG kit. | Evaluated specimens positive for ANA, CMV, dsDNA (SLE), EBV VCA, hCG (pregnancy), HIV, HSV-1, HSV-2, Influenza, Mumps, Myeloma, Parvovirus B19, Rheumatoid Factor, Rubella, Rubeola, T. gondii, VZV. The results demonstrated that the various disease state samples evaluated do not cross-react with the three (3) assays. Most positive results were confirmed by reference assays. Only one equivocal result was noted and not counted as discrepant. |
  | Correlation with CDC Evaluation Panels | Expectation of high agreement with CDC Reference Methods. | T. gondii IgG (N=100): BioPlex detected 70 Positives and 30 Negatives, matching CDC Reference Result (100% agreement).
  Rubella IgG (N=100): BioPlex detected 82 Positives and 18 Negatives across all 3 sites, matching CDC Reference Result (100% agreement).
  CMV IgG (N=100): BioPlex detected 60 Positives and 40 Negatives across all 3 sites, matching CDC Reference Result (100% agreement). |
  | Performance Characteristics (vs. Predicate EIA) | High positive and negative percent agreement (PPA/NPA) with predicate commercial immunoassays, with narrow 95% Confidence Intervals. Specific numerical thresholds for "high" are not explicitly stated, but the reported values demonstrate strong concordance. | Rubella IgG (Pregnant Women, N=300): Exclusion of equivocal: PPA 97.2% (276/284), NPA 100% (8/8). Inclusion of equivocal: PPA 94.5% (276/292), NPA 100% (8/8).
  Rubella IgG (Clinical Samples, N=400): Exclusion of equivocal: PPA 96.5% (358/371), NPA 100% (12/12). Inclusion of equivocal: PPA 92.7% (358/386), NPA 85.7% (12/14).
  T. gondii IgG (Total, N=700): PPA 97.5% (118/121), NPA 98.8% (569/576).
  CMV IgG (Total, N=700): PPA 99.0% (394/398), NPA 98.7% (298/302).
  CMV IgG (HIV+, N=100): PPA 100% (86/86), NPA 100% (14/14).
  Retrospective Rubella IgG (N=280): Exclusion of equivocal: PPA 92.8% (90/97), NPA 100% (124/124). Discordant samples were mostly low positive or close to cut-off for predicate. |

2. Sample Size Used for the Test Set and Data Provenance

The primary test sets for evaluating performance characteristics (agreement with predicate devices) are described as:

• Prospective Samples:
  • Pregnant Women: 300 samples (150 from the U.S., 150 from Europe).
  • Clinical Samples submitted for ToRC IgG testing: 1200 samples (400 for Rubella IgG, 700 for T. gondii IgG, 700 for CMV IgG - likely overlapping sets for the total of 1200).
  • Immunocompromised/AIDS patients (for CMV testing): 100 samples.
  • Provenance: Samples from the U.S. and Europe, some from specific clinical populations (pregnant women, immunocompromised/AIDS patients), and others from general clinical submissions. All appear to be prospective collections relative to the study.
• Retrospective Samples:
  • Rubella IgG: 280 samples (50 low positive, 50 high positive, 130 negative).
  • Provenance: Retrospective collection from U.S. clinical sites with known Rubella IgG status.
• CDC Evaluation Panels:
  • T. gondii IgG: 100 samples.
  • Rubella IgG: 100 samples.
  • CMV IgG: 100 samples.
  • Provenance: Provided by the Centers for Disease Control (CDC).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts

The ground truth for the test set was established primarily through comparison to predicate commercial immunoassays (e.g., bioMerieux VIDAS® TOXO IgG II, Rubella IgG, and CMV IgG kits) and CDC Reference Methods.

• Number of Experts: Not explicitly stated. For predicate assays, the "expert" is essentially the predicate test itself, which has previously undergone its own validation. For CDC Reference Methods, the expertise would be inherent in the established CDC methodology. There is no mention of individual experts reviewing results for ground truth establishment.
• Qualifications of Experts: Not applicable in the context of this document, as it relies on established assays and CDC reference methods rather than individual expert consensus.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving human review or consensus for discrepant results between the BioPlex 2200 ToRC IgG kit and the predicate devices. Instead, it reports percent agreements excluding equivocal results and including equivocal results from the BioPlex device. The discrepancies where the BioPlex 2200 disagreed with the predicate were simply reported as "Agreement" percentages. For the retrospective Rubella study, it's noted that "Most of the discordant samples were low positive or close to the cut-off for the predicate assay," providing some context, but not an adjudication process.

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

This is not applicable to this device. The BioPlex™ 2200 ToRC IgG kit is an automated in vitro diagnostic immunoassay system. It does not involve human "readers" interpreting images or clinical cases in a way that an MRMC study, typical for AI-powered diagnostic imaging, would be relevant. Its performance is evaluated against other diagnostic assays, not based on human interpretation improvement.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, the studies described are all standalone performance evaluations of the BioPlex™ 2200 ToRC IgG kit. The device is an automated system designed to provide results without human intervention in the assay interpretation step. The "Total" percentages of agreement with predicate assays represent the device's standalone performance.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth was established primarily using:

• Reference Devices/Predicate Assays: Results from other commercially available, FDA-cleared TOXO IgG, Rubella IgG, and CMV IgG immunoassays (bioMerieux VIDAS® kits) were used as the comparator "truth."
• CDC Reference Methods: For the correlation study, CDC-provided panels were used, with their results presumably representing a highly validated reference standard.

It is not based on pathology, expert consensus (beyond the validation of the reference assays themselves), or outcomes data.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for a "training set" in the context of developing the BioPlex 2200 ToRC IgG Kit. This type of immunoassay development typically involves extensive characterization and optimization using various reagent lots, calibrators, and control materials, rather than a "training set" in the machine learning sense. The performance studies described are for validation of the finalized device.

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

As there is no distinct "training set" described in the context of an algorithm or machine learning for this immunoassay, information on how its ground truth was established is not provided and is likely not applicable in the conventional sense for this type of device. The ground truth for the device's calibration and controls is established by defining concentrations or expected results for these internal control materials, which are then used to standardize assay performance.

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