The use of this reagent is indicated for the measurement of CO2 levels in serum or plasma on manual or automated systems. The measurement of serum or plasma CO2 content is useful in the assessment of disturbance of acid base balance in respiratory or metabolic acidosis and alkalosis

Device Description

This reagent is intended for the quantitative in vitro enzymatic determination of CO2 in serum or plasma on manual or automated systems. The method used in the present procedure is based on the following reactions. Carbon dioxide, in the form of bicarbonate ions, reacts with phosphoenolpyruvate (PEP) to form oxaloacetate and phosphate. This reaction is catalyzed by the enzyme phosphoenolpyruvate carboxylase (PEPC). PEP + HCO3- - PERC > oxaloacetate + H2PO4 This reaction is coupled with a second enzymatic reaction. Oxaloacetate, in the presence of malate dehydrogenase (MDH), is converted to malate, by reduced nicotinamide adenine dinucleotide (NADH). In this reaction one molecule of NADH is oxidized for each molecule of oxaloacetate present. oxaloacetate + NADH + H - MDH > malate + NAD The decrease in absorbance resulting from the oxidation of NADH is proportional to the original concentration of CO2 in the sample. Raichem wishes to market an extended stability formulation modification of the predicate device. Slight variations in the concentrations of ingredients were made to achieve an extended reconstituted stability of one year at 2 to 8 °C. The assay procedure and timing of the assay is the same as that of the predicate device.

AI/ML Overview

The provided document is a 510(k) submission for a medical device called "CO2 XL Reagent". This document focuses on demonstrating substantial equivalence to a predicate device and does not describe a study in the context of typical AI/ML device evaluations. Therefore, many of the requested categories are not applicable.

Here's an attempt to extract relevant information, with a strong emphasis on what is not present in the document.

Acceptance Criteria and Device Performance (as much as can be inferred from a 510(k) for a reagent):

The acceptance criteria for this type of device (a chemical reagent for in vitro diagnostic use) are typically centered around analytical performance parameters such as precision, accuracy (often demonstrated through comparison with a predicate device), and interference. The "device performance" reported is essentially the results of these analytical studies.

Acceptance Criteria Category	Specific Criteria (Inferred/Typical for Reagents)	Reported Device Performance (CO2 XL Reagent)
Precision	Coefficient of Variation (CV%) should be low, indicating reproducibility.	Manual Assay:Within Run: @ 15.7 mmol/L: CV = 4.3% @ 23.2 mmol/L: CV = 1.8%Total: @ 15.3 mmol/L: CV = 5.7% @ 23.2 mmol/L: CV = 2.3%Hitachi 717 Automated Assay: (Table headers are garbled, but implies precision studies were performed over 26 days following NCCLS EP5-T2, suggesting similar parameters would be evaluated and found acceptable.)
Accuracy / Comparison to Predicate	Strong correlation (high R, close to 1) and linear regression equation close to y = x, demonstrating agreement with the predicate device.	Comparison with Raichem CO2 Reagent (Manual Assay): Number of sample pairs: 65 Range: 4 - 40 mmol/L Correlation Coefficient: 0.993 Regression Equation: y = 0.988x + 0.43Automated Method (Hitachi 717) Comparison: Number of sample pairs: 107 Range: 7 - 46 mmol/L Correlation Coefficient: 0.998 Regression Equation: y = 0.976x + 0.487
Interference	No significant interference from common endogenous substances at physiologically relevant concentrations.	Bilirubin: No significant interference up to 20 mg/dL.Hemolysis (Hemoglobin): No significant interference up to 500 mg/dL.Lipemia (Triglycerides): No significant interference up to 3000 mg/dL.
Stability	Extended reconstituted stability of one year at 2 to 8 °C (This is the primary modification).	Implied to be met, as the modification goal was "extended reconstituted stability of one year at 2 to 8 °C." The document states "The product performance has been evaluated... The results of the comparative studies support the claim that the Raichem CO2 XL Reagent (modified device) is substantially equivalent..." thus implying this stability was successfully achieved and demonstrated.

Detailed Study Information (as requested, with noted applicability to this document):

Sample size used for the test set and the data provenance:
- Precision Studies:
  - Manual Assay: N=10 for each "Within Run" mean, N=20 for each "Total" mean. These are likely replicates of controls or patient samples tested multiple times.
  - Hitachi 717: Not explicitly stated, but "52 runs over a period of 26 days" implies a substantial number of measurements.
- Comparison Testing:
  - Manual Assay: 65 sample pairs.
  - Automated Method (Hitachi 717): 107 sample pairs.
- Interfering Substances: Not explicitly stated, but implied to be sufficient for testing the specified concentrations of bilirubin, hemoglobin, and triglycerides.
- Data Provenance: Not specified, but generally for such studies supporting a 510(k), the data would be generated in a laboratory setting (likely within the manufacturer's R&D or QA facilities) in the country of origin (USA, based on the address). The studies are prospective in the sense that they were designed and executed to evaluate the performance of the new reagent formulation.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Not Applicable. This is a chemical reagent. The "ground truth" for the performance studies is the quantitative value obtained from testing samples, either against a known standard, or via the predicate device. Expert interpretation of images or clinical data is not involved.
Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- Not Applicable. As above, no human interpretation requiring adjudication.
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 in vitro diagnostic reagent, not an AI/ML diagnostic aid for human readers.
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Not Applicable. This is a chemical reagent, not an algorithm or AI system. Its performance is inherent to the chemical reactions and measurement system.
The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- The "ground truth" in this context refers to the reference method or values against which the modified device's performance is compared.
  - For precision, the ground truth is the expected statistical distribution around a true mean value for a given sample or control.
  - For comparison studies, the "ground truth" for each sample is the measurement obtained using the predicate device. This establishes equivalence.
  - For interference studies, the ground truth is the expected result of a sample without the interfering substance, and the acceptance criteria define the allowable shift in result when the interfering substance is present.
The sample size for the training set:
- Not Applicable. This is a chemical reagent. There is no concept of a "training set" in the AI/ML sense. The formulation development process would involve extensive R&D and optimization, but this isn't analogous to training data for an algorithm.
How the ground truth for the training set was established:
- Not Applicable. Similar to the above, there is no "training set" or corresponding ground truth in the AI/ML context. The formulation (the "device") itself is the result of chemical and biochemical engineering principles, not machine learning from a dataset.

Summary

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JUN 2 4 1998

K982056

Page 1 of 4

CO2 XL Reagent

Special 510(k): Device Modification Summary

Submitter's Name/Contact Person l.

Melissa A. Saner/Manager

Address

Raichem Division of Hemagen Diagnostics Inc. # 2022395 Formerly: Reagents Applications, Inc. 8225 Mercury Court San Diego, CA 92129 Phone: 619-569-8009 Fax: 619-569-6208

Date Prepared

June 1, 1998

ll. Device Name

Trade Name: Common Name: Classification Name: Device Classification: Regulation Number: Panel:

CO2 XL Reagent Carbon Dioxide Bicarbonate/carbon dioxide Test System ll 21 CFR 862.1160 Chemistry (75) CDT

111. Predicate (Cleared) Device

CO2 Reagent: 510(k) Docket No. K854544 Manufactured By: Raichem Division of Hemagen Diagnostics Inc. (Reagents Applications, Inc.) Submitted Bv: Reagents Applications, Inc.

IV. Description of Modified Device

This reagent is intended for the quantitative in vitro enzymatic determination of CO2 in serum or plasma on manual or automated systems.

The method used in the present procedure is based on the following reactions. Carbon dioxide, in the form of bicarbonate ions, reacts with phosphoenolpyruvate (PEP) to form oxaloacetate and phosphate. This reaction is catalyzed by the enzyme phosphoenolpyruvate carboxylase (PEPC).

PEP + HCO3- - PERC > oxaloacetate + H2PO4

This reaction is coupled with a second enzymatic reaction. Oxaloacetate, in the presence of malate dehydrogenase (MDH), is converted to malate, by reduced nicotinamide adenine dinucleotide (NADH). In this reaction one molecule of NADH is oxidized for each molecule of oxaloacetate present.

oxaloacetate + NADH + H - MDH > malate + NAD

The decrease in absorbance resulting from the oxidation of NADH is proportional to the original concentration of CO2 in the sample.

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Raichem wishes to market an extended stability formulation modification of the predicate device. Slight variations in the concentrations of ingredients were made to achieve an extended reconstituted stability of one year at 2 to 8 °C. The assay procedure and timing of the assay is the same as that of the predicate device.

Intended Use of Modified Device V.

This reagent is intended for the quantitative in vitro enzymatic determination of CO₂ in serum or plasma on manual or automated systems. The measurement of serum or plasma CO2 content is useful in the assessment of disturbances of acid-base balance in respiratory or metabolic acidosis and alkalosis.

VI. Substantial Equivalence

Modified Device

This reagent is intended for the quantitative in vitro enzymatic determination of CO₂ in serum or plasma on manual or automated systems.

PEP + HCO3 - PEPC > oxaloacetate + H2PO4

oxaloacetate + NADH + H - MOR > malate + NAD

The decrease in absorbance resulting from the oxidation of NADH is proportional to the original concentration of CO2 in the sample.

Predicate (Cleared) Device

Raichem CO2 Reagent is intended for the quantitative in vitro enzymatic determination of CO2 content in serum or plasma.

The following enzymatic reactions are involved in the assay: Carbon dioxide (in the form of bicarbonate ions) reacts with phosphoenolpyruvate (PEP) to form oxaloacetate and phosphate. This reaction is catalyzed by the enzyme phosphoenolpyruvate carboxylase (PEPC).

PEP + HCO3 - PEPC > oxaloacetate + H2PO4

This reaction is coupled with another enzymatic reaction in which oxaloacetate, in the presence of malate dehydrogenase (MDH), is converted to malate, by reduced nicotinamide adenine dinucleotide (NADH). In this reaction one molecule of NADH is oxidized for each molecule of oxaloacetate present.

oxaloacetate + NADH + H - MDH > malate + NAD The decrease in absorbance resulting from the oxidation of NADH is proportional to the original concentration of CO2 in the sample.

Summary

The intended use and the fundamental scientific technology of the device remain the same. The CO2 XL Reagent (modified device) is substantially equivalent to the predicate (cleared) device.

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Performance Data VII.

Precision

Manual Assay

Within Run
Mean (mmol/L)	15.7	23.2
SD	0.7	0.4
CV (%)	4.3	1.8
N	10	10
Total
Mean (mmol/L)	15.3	23.2
SD	0.9	0.5
CV (%)	5.7	2.3
N	20	20

Hitachi 717

Precision studies were performed in 52 runs over a period of 26 days following the NCCLS EP5-T2 Tentative Guideline.

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Comparison Testing

Comparison with Raichem CO2 Reagent (510(k) No. K854544)

Number of sample pairs	65
Range of results (mmol/L):	4 - 40
Correlation Coefficient :	0.993
Regression Equation:	y = 0.988x + 0.43
Note: where x = CO2 Reagent, y = CO2 XL Reagent

Automated Method (Hitachi 717) Comparison with Raichem CO2 Reagent (510(k) No. K854544) on Hitachi 717 following the NCCLS EP9-A Approved Guideline

Number of sample pairs	107
Range of results (mmol/L):	7 - 46
Correlation Coefficient :	0.998
Regression Equation:	y = 0.976x + 0.487
Note: where x = CO2 Reagent, y = CO2 XL Reagent

Interfering Substances

Interference from bilirubin, hemolysis, and lipemia was evaluated in accordance with NCCLS EP7-P.

Bilirubin: No significant interference observed up to 20 mg/dL of bilirubin. Hemolysis (Hemoglobin): No significant interference observed up to 500 mg/dL of hemoglobin.

Lipemia: No significant interference observed up to 3000 mg/dL of triglycerides.

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Summary

The product performance has been evaluated by both manual and automated analyzer methods. The results of the comparative studies support the claim that the Raichem CO2 XL Reagent (modified device) is substantially equivalent to the predicate (cleared) device.

The safety and effectiveness information upon which the substantial equivalence determination is based has been enclosed with this submission. This has been prepared in accordance with the requirements of the SMDA 1990 and 21 CFR Sections 807.87.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/2 description: The image shows the logo for the Department of Health & Human Services - USA. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the top half of the circle. The bottom half of the circle contains a stylized image of an eagle.

JUN 2 4

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Melissa A. Saner Manaqer RAICHEM Division of Hemagen Diagnostics 8225 Mercury Court San Diego, CA 92111

K982056 Re : Trade Name: CO2 XL Reagent Application Requlatory Class: II Product Code: CDT June 2, 1998 Dated: Received: June 9, 1998

Dear Ms. Saner:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use acvice in babbantosure) 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). 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 (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in _ regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.

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 (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or at (301) 443-6597, or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".

Sincerely yours,

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

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Device Name:

CO2 XL Reagent

Indication(s) For Use

(PLEASE DO NOT WRITE BELOW THIS LINE)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Clive Xuri

(Division Sign-Off) (Division of Clinical Laboratory Devices 1982056 510(k) Number.

Prescription Use V (Per 21 CFR 801.109)

Over-The-Counter-Use

Regulation Number and Section

§ 862.1160 Bicarbonate/carbon dioxide test system.

(a)
Identification. A bicarbonate/carbon dioxide test system is a device intended to measure bicarbonate/carbon dioxide in plasma, serum, and whole blood. Bicarbonate/carbon dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance.(b)
Classification. Class II.