G7 AUTOMATED HPLC ANALYZER, BETA-THALASSEMIA MODE

K020489 · Tosoh Medics, Inc. · JPD · May 14, 2002 · Hematology

Device Facts

• Record ID: K020489
• Device Name: G7 AUTOMATED HPLC ANALYZER, BETA-THALASSEMIA MODE
• Applicant: Tosoh Medics, Inc.
• Product Code: JPD · Hematology
• Decision Date: May 14, 2002
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.7400
• Device Class: Class 2

Intended Use

The G7 Automated HPLC Analyzer: Beta-thalassemia Mode is intended for IN VITRO DIAGNOSTIC USE ONLY for the separation and area percent determinations of hemoglobins A2 and F and as an aid in the detection and presumptive identification of abnormal hemoglobins in whole blood using ion-exchange high performance liquid chromatography (HPLC). The G7 Automated HPLC Analyzer: Beta-thalassemia Mode reagents and software are intended only for use on the Tosoh G7 Automated HPLC Analyzer.

Device Story

G7 Automated HPLC Analyzer: Beta-thalassemia Mode is an automated ion-exchange HPLC system for clinical laboratory use. Input: EDTA whole blood samples. Operation: Automated sampling unit, liquid pump, degasser, and cation exchange column separate hemoglobin fractions via salt concentration gradient elution. Detection: Colorimetric measurement at 415 nm. Output: Quantitative area percentages for HbA2 and HbF; chromatographic tracings; presumptive identification of hemoglobin variants (e.g., A, F, S, C, D) based on retention time windows. Data management: On-board printer, floppy disk storage, and RS232 host computer transmission. Clinical utility: Aids clinicians in diagnosing hemoglobinopathies by providing quantitative hemoglobin profiles and identifying abnormal patterns. Benefits: Automated processing reduces manual labor and improves consistency in hemoglobin analysis compared to traditional electrophoresis or manual chromatography.

Clinical Evidence

Clinical performance evaluated via comparative analysis of patient samples. HbA2 quantitation (n=75) compared to micro-chromatographic method showed slope 0.9318, r=0.9318. HbF quantitation (n=57) compared to HPLC method showed slope 0.778, r=0.9906. Qualitative identification of hemoglobin variants (n=155) compared to electrophoresis showed high concordance. Precision studies: intra-assay CVs 4.3-13.5% (HbF) and 1.3-2.1% (HbA2); between-day CVs 2.2-7.7% (HbF) and 2.4-3.3% (HbA2). Recovery: 99.4-107.1%.

Technological Characteristics

Automated HPLC system using cation exchange column. Energy source: electrical (microprocessor-controlled). Connectivity: RS232 port for host computer. Form factor: benchtop analyzer with sampling unit, pump, degasser, detector, and printer. Software: microprocessor-controlled, floppy disk-loaded. Detection: 415 nm colorimetric. Reagents: elution buffers with salt gradients.

Indications for Use

Indicated for in vitro diagnostic use in patients requiring quantitative measurement of Hemoglobin A2 and F and presumptive identification of abnormal hemoglobins in EDTA whole blood samples.

Regulatory Classification

Identification

A hemoglobin A2 assay is a device used to determine the hemoglobin A2 content of human blood. The measurement of hemoglobin A2 is used in the diagnosis of the thalassemias (hereditary hemolytic anemias characterized by decreased synthesis of one or more types of hemoglobin polypeptide chains).

Predicate Devices

• HbA2: Beta-Thal HbA2 Quik Column (K823870)
• HbF: VARIANT BETA-THALASSEMIA SHORT PROGRAM (K924122)
• Presumptive Hb identification: Beckman Paragon Electrophoresis (K802821)

Submission Summary (Full Text)

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1020489

MAY 1 4 2002

Image /page/0/Picture/2 description: The image shows the logo for Tosoh Medics, Inc. The logo consists of a stylized four-leaf clover shape with a square in the center, followed by the text "TOSOH MEDICS, INC." to the right. Below the clover shape is the text "TOSOH" with a horizontal line underneath.

# 510(k) Summary

# Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode

| Submitter: | Tosoh Medics, Inc.<br>347 Oyster Point Blvd., Suite 201<br>South San Francisco, CA 94080<br>Phone: [phone]<br>Fax: [phone] |
|------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|
| Contact Person: | Lois Nakayama<br>Manager, Quality Assurance |
| Date of Summary Preparation: | February 8, 2002 |
| Device Name: | G7 Automated HPLC Analyzer: Beta-<br>thalassemia Mode |
| Classification Name: | Class II, JPD<br>21 CFR 864.7400<br>Hemoglobin A2 quantitation |
| Predicate Device: | HbA2: Beta-Thal HbA2 Quik ColumnTM<br>Helena Laboratories<br>Beaumont, TX<br>K823870 |
| | HbF: VARIANT BETA-THALASSEMIA<br>SHORT PROGRAM<br>Bio-Rad Laboratories<br>Hercules, CA<br>K924122 |
| | Presumptive Hb identification:<br>Beckman Paragon® Electrophoresis<br>Beckman Instruments, Inc.<br>Fullerton, CA<br>K802821 |

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## Device Description:

The G7 Automated HPLC Analyzer and the HbA1c Variant Analysis Mode reagent system and software have previously cleared by the Food and Drug Administration (K011434). The subject of this submission is merely the reagent system/software specific for the Beta-thalassemia Mode that is intended for the separation and area percent determinations of hemoglobins A2 and F and as an aid in the detection and presumptive identification of abnormal hemoglobins in whole blood using ion-exchange high performance liquid chromatography (HPLC).

The G7 Automated HPLC Analyzer - Beta-thalassemia Mode is an automated High Performance Liquid Chromatography (HPLC) system that separates and reports HbF and HbA2 quantitative percentages in whole blood. A chromatographic tracing of the hemoglobin products found in the sample is also produced which allows for the comparison of an individual chromatogram with standard patterns of known composition. The operational portion of the G7 Beta-thalassemia Mode is composed of a sampling unit, liquid pump, degasser, detector, microprocessors, sample loader, floppy disk drive unit, operational panel and a printer all of which have already been cleared by the FDA (K011434). The reagents and software program specific to the Beta-thalassemia Mode consist of calibrators, elution buffers, column and software only.

The G7 Automated HPLC System - Beta-thalassemia Mode uses a cation exchange column and separates the hemoglobin in the blood into fractions. The separation is accomplished by eluting the hemoglobins from the column with a gradient of three elution buffers containing increasing salt concentrations. The resulting report is printed out on the on-board printer and can be stored on a floppy disk in the on-board floppy disk drive. The data can also be transmitted to a host computer through the RS232 port. The result report includes a sample ID, date, time, area percentages and retention time in minutes of each individual peak detected. Peaks that meet the retention time "windows" pre-set in the software are labeled as F, A0, A2, D+, S+, C+. All others are designated in order of appearance as PXX and are listed in order of appearance.

All automated processes in the G7 Beta-thalassemia Mode are controlled by internal microprocessors using software downloaded via the on-board floppy disk drive.

#### Statement of Intended Use:

The G7 Automated HPLC Analyzer: Beta-thalassemia Mode is intended for IN VITRO DIAGNOSTIC USE ONLY for the separation and area percent determinations of hemoglobins A2 and F and as an aid in the detection and presumptive identification of abnormal hemoglobins in whole blood using ion-exchange high performance liquid chromatography (HPLC).

The G7 Automated HPLC Analyzer: Beta-thalassemia Mode reagents and software are intended only for use on the Tosoh G7 Automated HPLC Analyzer.

#### Substantial Equivalence:

#### Comparison Data

The Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode is substantially equivalent in intended use to instrument and reagent systems in commercial distribution

Image /page/1/Picture/11 description: The image shows the logo for TOSOH. The logo consists of the word "TOSOH" in a simple, sans-serif font, with the letters stacked vertically. Above the text is a stylized graphic element that appears to be a square with rounded corners, with the top left corner filled in black and the rest of the shape in white.

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that are used to quantitate Hemoglobin A2 and Hemoglobin F in whole blood and qualitatively identify clinically important abnormal human hemoglobins.

Specifically, the Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode is substantially equivalent to the Helena Laboratories, Inc. (Beaumont, TX) Beta-Thal HbA2 Quik Column™ (K823870) method for quantitating Hemoglobin A2 and is substantially equivalent to the Bio-Rad Laboratories (Hercules, CA) VARIANT™ BETA-THALASSEMIA SHORT PROGRAM for quantitatiing Hemoglobin F (K924122) and to the Beckman Paragon® Hemoglobin Electrophoresis as an aid in identifying broad presumptive classes of abnormal human hemoglobins. A summary comparison of the capabilities and specifications of these systems is provided below in Table 1, Table 2 and Table 3.

| Table 1 |
|-------------------------------------------------------------|
| Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode HbA |
| vs. |
| Helena Quik ColumnTM HbA2 |

| | G7 Automated HPLC<br>Analyzer: Beta-thal Mode | Beta-Thal HbA2 Quik<br>Column™ |
|---------------------------|----------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|
| Intended Use | Quantitative measurement<br>of HbA2 in whole blood | Quantitative measurement<br>of HbA2 in whole blood |
| Methodology | High Performance Liquid<br>Chromatography using<br>cation exchange | Micro-chromatographic<br>technique using anion<br>exchange |
| Separation Method | Based on differences in<br>electrical charge between<br>column material and<br>hemogoblin molecule | Based on differences in<br>electrical charge between<br>column material and<br>hemoglobin molecules |
| Sample Type | EDTA whole blood | EDTA whole blood |
| Microprocessor Controlled | YES | NO |
| Automatic Sampling | YES | NO |
| Elution Method | Buffers with differing salt<br>concentrations causing an<br>elution gradient | Buffers with differing salt<br>concentrations causing an<br>elution gradient |
| End Point | Colorimetric measurement<br>at 415 nm | Colorimetric measurement<br>at 415 nm |
| Results | Quantitative HbA2 Area % | Quantitative HbA2 Area % |
| Normal Reference Interval | 1.7 - 2.9 % | 2.2 - 3.3 % |
| Imprecision | 2.4 - 3.3 % | 3.25 % |
| Upper Linearity Limit | Up to 12.8 % | Not given |

Image /page/2/Picture/4 description: The image shows a logo with the text "TOSOH" underneath. The logo is a black shape resembling a four-leaf clover with rounded edges. In the center of the clover shape is a white square.

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Table 2 Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode HbF VS. Bio-Rad Laboratories VARIANT™ BETA-THALASSEMIA SHORT PROGRAM HbF

| | G7 Automated HPLC Analyzer: Beta-thal Mode | VARIANT™ BETA-THALASSEMIA SHORT PROGRAM |
|-------------------------------|-------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| Intended Use | Quantitative measurement of HbF in whole blood | Quantitative measurement of HbF in whole blood |
| Methodology | High Performance Liquid Chromatography using cation exchange | High Performance Liquid Chromatography using cation exchange |
| Separation Method | Based on differences in electrical charge between column material and hemogoblin molecule | Based on differences in electrical charge between column material and hemoglobin molecules |
| Sample Type | EDTA whole blood | EDTA whole blood |
| Microprocessor Controlled | YES | YES |
| Automatic Sampling | YES | YES |
| Calibration | One Point Dual Analyte Calibration | One Point Dual Analyte Calibration |
| Automated Sample Pretreatment | YES | NO |
| Elution Method | Buffers with differing salt concentrations causing an elution gradient | Buffers with differing salt concentrations causing an elution gradient |
| End Point | Colorimetric measurement at 415 nm | Colorimetric measurement at 415 nm |
| Results | Quantitative HbF Area % | Quantitative HbF Area % |
| Normal Reference Interval | 0.5 - 1.9 | 2.2 - 7.7 % |
| Imprecision (Intra-assay) | 2.2 -7.7 % | Not given |
| Upper Linearity(Reportable) | Up to 35.0 % | Up to 40% |

Image /page/3/Picture/2 description: The image shows a logo with a stylized cross shape in black, with a white square in the center. The cross shape has rounded edges, giving it a soft appearance. Below the logo, the word "TOSOH" is printed in a simple, sans-serif font. The logo appears to be a corporate symbol, possibly for a company or organization.

_

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## Table 3 Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode VS. Beckman Paragon® Hemoglobin Electrophoresis

| | G7 Automated HPLC<br>Analyzer: Beta-thal Mode | Hemoglobin<br>Electrophoresis |
|----------------------------------|----------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|
| Intended Use | Aid in the identification of<br>abnormal human<br>hemoglobins | Electrophoretic separation<br>of human hemoglobins to<br>screen for clinically<br>important hemoglobin<br>variants |
| Methodology | High Performance Liquid<br>Chromatography using<br>cation exchange | Electrophoresis |
| Separation Method | Based on differences in<br>electrical charge between<br>column material and<br>hemoglobin molecule | Based on differences in<br>electrical charge between<br>the media and hemoglobin<br>molecules |
| Sample Type | EDTA whole blood | EDTA whole blood |
| Microprocessor Controlled | YES | NO |
| Automatic Sampling | YES | NO |
| Calibration | Software "windows" for<br>various hemoglobin<br>components are preset | Comparison of unknown<br>with samples of known<br>content |
| Automated Sample<br>Pretreatment | YES | NO |
| Elution Method | Buffers with differing salt<br>concentrations causing an<br>elution gradient | Buffers with differing salt<br>concentrations causing an<br>elution gradient |
| End Point | Colorimetric measurement<br>at 415 nm | Densitometer quantitation<br>or visual interpretation of<br>patterns obtained |
| Results | Presumptive identification<br>of certain hemoglobin<br>variants as "A", "F", "S", "C",<br>and "D" or "unknown" | Qualitative presumptive<br>identification of hemoglobin<br>variants "A", "F", "S", "C" or<br>"unknown" |
| Normal Reference Interval | Compared to "normal"<br>pattern | Compared to "normal"<br>pattern |

Image /page/4/Picture/2 description: The image shows a logo with the text "TOSOH" below it. The logo is a black shape resembling a four-leaf clover with rounded edges. In the center of the clover shape, there is a white square. The text "TOSOH" is in a simple, sans-serif font.

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## Comparative Analysis

## Comparative Analysis Quantitative HbA2

Patient specimens were analyzed using the Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode and another commercially available quantitative HbA2 assay utilizing a micro-chromatographic methodology (Helena Laboratories' Beta-Thal HbA2 Quik Column™. Approximately onehalf the samples had HbA2 within the normal reference interval. The remainder showed elevated results. The comparison yielded the following correlation statistics when the two methods were compared using linear regression analysis:

| Slope: | 0.9318 |
|--------------------------|------------|
| Y-Intercept: | -1.08 |
| Correlation Coefficient: | 0.9318 |
| Range of Samples (%): | 1.6 – 7.4% |
| n: | 75 |

#### Comparative Analysis Quantitative HbF

Patient specimens were analyzed with the Tosoh G7 Automated HPLC Analyzer: Beta-thalassemia Mode and another commercially available quantitative HbF assay utilizing HPLC (Bio-Rad Laboratories VARIANT BETA-THALASSEMIA SHORT PROGRAM. The comparison yielded the following correlation statistics between these two methods.

| Slope: | 0.778 |
|--------------------------|------------|
| Y-Intercept: | 1.15 |
| Correlation Coefficient: | 0.9906 |
| Range of Samples (%): | 0.5 – 67.6 |
| n: | 57 |

Image /page/5/Picture/7 description: The image shows the word "TOSOH" in a sans-serif font below a black abstract shape. The shape resembles a four-leaf clover with rounded edges, and it has a white square in the center. The black shape is symmetrical and appears to be a stylized logo.

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# Qualitative Comparison of Hemoglobins in Clinical Samples

Whole blood from patients suspected of having hemoglobinopathies were tested on the G7 Automated HPLC Analyzer: Beta-thalassemia Mode and the Beckman Laboratories Paragon® Hemoglobin Electrophoresis. Results from these qualitative comparisons are listed below.

| G7 Presumptive Result | Electrophoresis Result | Number of Analyses |
|---------------------------------------------|------------------------|--------------------|
| HbA/HbS* | HbA/HbS* | 37 |
| HbA/HbS*/HbA2* | HbA/HbS*/HbA2* | 1 |
| HbF*/HbS* | HbF*/HbS* | 1 |
| HbS*/HbC* | HbS*/HbC* | 2 |
| HbA/HbC* | HbA/HbC* | 11 |
| HbA/HbC*/HbF* | HbA/HbC*/HbF* | 1 |
| HbA/HbS*/HbF* | HbA/HbS*/HbF* | 1 |
| HbA/HbD* | HbA/HbD* | 7 |
| HbA/HbD*/HbF* | HbA/HbD*/HbF* | 1 |
| HbA/Hb Unknown | HbA/HbE* | 5 |
| HbA/unknown coeluting<br>with HbA2* (47.2%) | HbA/unknown | 1 |
| HbA/HbF*/Unknown fast* | HbA/HbF*/Hb Barts* | 1 |
| HbA/Hb Unknown* | HbA/Hb unknown* | 1 |
| HbA/HbA2*/HbF* | HbA/HbA2*/HbF* | 3 |
| HbA/HbA2*/HbF | HbA/HbA2*/HbF | 9 |
| HbF*/HbA/HbA2 | HbF*/HbA/HbA2 | 7 |
| HbF*/HbA/HbA2* | HbF/HbA/HbA2* | 6 |
| HbA/Hb Unknown* | HbA/HbG* | 5 |
| Normal HbA/HbF/HbA2 | Normal HbA/HbF/HbA2 | 55 |
| | TOTAL COMPARISONS | 155 |

Precision studies demonstrated intra-assay precision % CVs on HbF of 4.3 - 13.5% and on HbA2 from 1.3 - 2.1 %. Between day precision CV%s of2.2 -- 7.7% on HbF and on HbA2 2.4 -- 3.3 %. Recovery studies performed on HbF and HbA2 showed recoveries ranging from 99.4% - 107.1%.

Image /page/6/Picture/4 description: The image shows the logo for TOSOH. The logo consists of a stylized four-leaf clover shape in black, with a white square in the center. Below the logo, the word "TOSOH" is printed in a simple sans-serif font.

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### Conclusion:

Considering the excellent correlation between the Tosoh G7 Automated HPLC Analyzer: Betathalassemia Mode and the other predicate devices listed above, it can be concluded that the G7 Automated HPLC Analyzer: Beta-thalassemia Mode is substantially equivalent to the other predicate devices which have been 510(K) cleared. Based on the establishment of substantial equivalence, the safety and effectiveness of the Tosoh G7 Automated HPLC Analyzer: Betathalassemia Mode is confirmed.

Image /page/7/Picture/2 description: The image shows the word "TOSOH" in all capital letters. Above the word is a black abstract shape with a white square in the center. The shape appears to be a stylized plus sign with rounded edges.

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## DEPARTMENT OF HEALTH & HUMAN SERVICES

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# MAY 1 4 2002

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Ms. Lois Nakayama Manager, Ouality Assurance TOSOH Medics, Inc. 347 Oyster Point Boulevard, Suite 201 South San Francisco, California 94080

k020489 Re:

Trade/Device Name: G7 Automated HPLC Analyzer: Beta-thalassemia Mode Regulation Number: 21 CFR § 864.7400 Regulation Name: Hemoglobin A2 quantitation Regulatory Class: II Product Code: JPD Dated: April 29, 2002 Received: May 1, 2002

Dear Ms. Nakayama:

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.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); 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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Page 2

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at [phone]. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at [phone]. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers International and Consumer Assistance at its toll-free number [phone] or [phone] or at its internet address "http://www.fda.gov/cdrb/dsma/dsmamain.html".

Sincerely vours.

Steven Butman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Image /page/10/Picture/0 description: The image shows the logo for Tosoh Medics, Inc. The logo consists of a black four-leaf clover-like shape with a white square in the center, followed by the text "TOSOH MEDICS, INC." to the right. Below the clover is the word "TOSOH" with a horizontal line underneath.

## PREMARKET NOTIFICATION

## INDICATION FOR USE STATEMENT

# G7 Automated HPLC Analyzer: Beta-thalassemia Mode

The G7 Automated HPLC Analyzer: Beta-thalassemia Mode is intended for IN VITRO DIAGNOSTIC USE ONLY for the separation and area percent determinations of hemoglobins A2 and F and as an aid in the detection and presumptive identification of abnormal hemoglobins in whole blood using ionexchange high performance liquid chromatography (HPLC).

The G7 Automated HPLC Analyzer: Beta-thalassemia Mode reagents and software are intended only for use on the Tosoh G7 Automated HPLC Analyzer.

Josephine Bautista.

(Division Sign-Off)
Division of Clinical Laboratory Devices

510(k) Number K020489